annotation_CSV/PMC4888278.csv

anno_start	anno_end	anno_text	entity_type	sentence	section
36	44	RORgamma	protein	Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand	TITLE
95	108	benzoxazinone	chemical	Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand	TITLE
4	28	nuclear hormone receptor	protein_type	The nuclear hormone receptor RORγ regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.	ABSTRACT
29	33	RORγ	protein	The nuclear hormone receptor RORγ regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.	ABSTRACT
117	128	interleukin	protein_type	The nuclear hormone receptor RORγ regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.	ABSTRACT
129	134	IL-17	protein_type	The nuclear hormone receptor RORγ regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.	ABSTRACT
33	37	RORγ	protein	This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins.	ABSTRACT
103	136	activation function 2 (AF2) helix	structure_element	This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins.	ABSTRACT
144	165	ligand binding domain	structure_element	This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins.	ABSTRACT
169	173	RORγ	protein	This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins.	ABSTRACT
180	189	conserved	protein_state	This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins.	ABSTRACT
190	207	LXXLL helix motif	structure_element	This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins.	ABSTRACT
26	30	RORγ	protein	Our goal was to develop a RORγ specific inverse agonist that would help down regulate pro-inflammatory gene transcription by disrupting the protein protein interaction with coactivator proteins as a therapeutic agent.	ABSTRACT
40	55	inverse agonist	protein_state	Our goal was to develop a RORγ specific inverse agonist that would help down regulate pro-inflammatory gene transcription by disrupting the protein protein interaction with coactivator proteins as a therapeutic agent.	ABSTRACT
42	55	benzoxazinone	chemical	We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay.	ABSTRACT
74	81	agonist	protein_state	We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay.	ABSTRACT
83	89	BIO592	chemical	We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay.	ABSTRACT
95	110	inverse agonist	protein_state	We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay.	ABSTRACT
112	118	BIO399	chemical	We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay.	ABSTRACT
140	156	FRET based assay	experimental_method	We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay.	ABSTRACT
17	26	AF2 helix	structure_element	We show that the AF2 helix of RORγ is proteolytically sensitive when inverse agonist BIO399 binds.	ABSTRACT
30	34	RORγ	protein	We show that the AF2 helix of RORγ is proteolytically sensitive when inverse agonist BIO399 binds.	ABSTRACT
38	63	proteolytically sensitive	protein_state	We show that the AF2 helix of RORγ is proteolytically sensitive when inverse agonist BIO399 binds.	ABSTRACT
69	84	inverse agonist	protein_state	We show that the AF2 helix of RORγ is proteolytically sensitive when inverse agonist BIO399 binds.	ABSTRACT
85	91	BIO399	chemical	We show that the AF2 helix of RORγ is proteolytically sensitive when inverse agonist BIO399 binds.	ABSTRACT
6	27	x-ray crystallography	experimental_method	Using x-ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORγ.	ABSTRACT
67	80	benzoxazinone	chemical	Using x-ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORγ.	ABSTRACT
81	88	agonist	protein_state	Using x-ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORγ.	ABSTRACT
89	95	BIO592	chemical	Using x-ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORγ.	ABSTRACT
123	127	RORγ	protein	Using x-ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORγ.	ABSTRACT
9	31	in vivo reporter assay	experimental_method	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
50	65	inverse agonist	protein_state	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
66	72	BIO399	chemical	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
99	103	RORγ	protein	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
109	112	ROR	protein_type	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
132	133	α	protein	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
138	139	β	protein	Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORγ over ROR sub-family members α and β.	ABSTRACT
14	27	benzoxazinone	chemical	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
54	64	FRET assay	experimental_method	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
73	80	agonist	protein_state	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
82	88	BIO592	chemical	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
93	108	inverse agonist	protein_state	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
110	116	BIO399	chemical	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
161	168	agonist	protein_state	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
185	189	RORγ	protein	The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORγ.	ABSTRACT
35	44	AF2 helix	structure_element	The proteolytic sensitivity of the AF2 helix of RORγ demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site.	ABSTRACT
48	52	RORγ	protein	The proteolytic sensitivity of the AF2 helix of RORγ demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site.	ABSTRACT
92	98	BIO399	chemical	The proteolytic sensitivity of the AF2 helix of RORγ demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site.	ABSTRACT
99	114	inverse agonist	protein_state	The proteolytic sensitivity of the AF2 helix of RORγ demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site.	ABSTRACT
138	170	coactivator protein binding site	site	The proteolytic sensitivity of the AF2 helix of RORγ demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site.	ABSTRACT
4	28	structural investigation	experimental_method	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
36	42	BIO592	chemical	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
43	50	agonist	protein_state	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
55	61	BIO399	chemical	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
62	77	inverse agonist	protein_state	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
78	88	structures	evidence	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
108	114	Met358	residue_name_number	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
118	122	RORγ	protein	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
142	146	RORγ	protein	Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORγ as the trigger for RORγ specific inverse agonism.	ABSTRACT
0	38	Retinoid-related orphan receptor gamma	protein	Retinoid-related orphan receptor gamma (RORγ) is a transcription factor belonging to a sub-family of nuclear receptors that includes two closely related members RORα and RORβ.	INTRO
40	44	RORγ	protein	Retinoid-related orphan receptor gamma (RORγ) is a transcription factor belonging to a sub-family of nuclear receptors that includes two closely related members RORα and RORβ.	INTRO
51	71	transcription factor	protein_type	Retinoid-related orphan receptor gamma (RORγ) is a transcription factor belonging to a sub-family of nuclear receptors that includes two closely related members RORα and RORβ.	INTRO
101	118	nuclear receptors	protein_type	Retinoid-related orphan receptor gamma (RORγ) is a transcription factor belonging to a sub-family of nuclear receptors that includes two closely related members RORα and RORβ.	INTRO
161	165	RORα	protein	Retinoid-related orphan receptor gamma (RORγ) is a transcription factor belonging to a sub-family of nuclear receptors that includes two closely related members RORα and RORβ.	INTRO
170	174	RORβ	protein	Retinoid-related orphan receptor gamma (RORγ) is a transcription factor belonging to a sub-family of nuclear receptors that includes two closely related members RORα and RORβ.	INTRO
68	72	RORs	protein_type	Even though a high degree of sequence similarity exists between the RORs, their functional roles in regulation for physiological processes involved in development and immunity are distinct.	INTRO
20	24	RORγ	protein	During development, RORγ regulates the transcriptional genes involved in the functioning of multiple pro-inflammatory lymphocyte lineages including T helper cells (TH17cells) which are necessary for IL-17 production.	INTRO
199	204	IL-17	protein_type	During development, RORγ regulates the transcriptional genes involved in the functioning of multiple pro-inflammatory lymphocyte lineages including T helper cells (TH17cells) which are necessary for IL-17 production.	INTRO
0	5	IL-17	protein_type	IL-17 is a pro-inflammatory interleukin linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease; making its transcriptional regulation through RORγ an attractive therapeutic target.	INTRO
28	39	interleukin	protein_type	IL-17 is a pro-inflammatory interleukin linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease; making its transcriptional regulation through RORγ an attractive therapeutic target.	INTRO
197	201	RORγ	protein	IL-17 is a pro-inflammatory interleukin linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease; making its transcriptional regulation through RORγ an attractive therapeutic target.	INTRO
0	4	RORγ	protein	RORγ consists of an N-terminal DNA binding domain (DBD) connected to a C-terminal ligand binding domain (LBD) via a flexible hinge region.	INTRO
31	49	DNA binding domain	structure_element	RORγ consists of an N-terminal DNA binding domain (DBD) connected to a C-terminal ligand binding domain (LBD) via a flexible hinge region.	INTRO
51	54	DBD	structure_element	RORγ consists of an N-terminal DNA binding domain (DBD) connected to a C-terminal ligand binding domain (LBD) via a flexible hinge region.	INTRO
82	103	ligand binding domain	structure_element	RORγ consists of an N-terminal DNA binding domain (DBD) connected to a C-terminal ligand binding domain (LBD) via a flexible hinge region.	INTRO
105	108	LBD	structure_element	RORγ consists of an N-terminal DNA binding domain (DBD) connected to a C-terminal ligand binding domain (LBD) via a flexible hinge region.	INTRO
125	137	hinge region	structure_element	RORγ consists of an N-terminal DNA binding domain (DBD) connected to a C-terminal ligand binding domain (LBD) via a flexible hinge region.	INTRO
4	7	DBD	structure_element	The DBD is composed of two zinc fingers that allow it to interact with specifically encoded regions on the DNA called the nuclear receptor response elements.	INTRO
27	39	zinc fingers	structure_element	The DBD is composed of two zinc fingers that allow it to interact with specifically encoded regions on the DNA called the nuclear receptor response elements.	INTRO
122	156	nuclear receptor response elements	structure_element	The DBD is composed of two zinc fingers that allow it to interact with specifically encoded regions on the DNA called the nuclear receptor response elements.	INTRO
4	7	LBD	structure_element	The LBD consists of a coactivator protein binding pocket and a hydrophobic ligand binding site (LBS) which are responsible for regulating transcription.	INTRO
22	56	coactivator protein binding pocket	site	The LBD consists of a coactivator protein binding pocket and a hydrophobic ligand binding site (LBS) which are responsible for regulating transcription.	INTRO
63	94	hydrophobic ligand binding site	site	The LBD consists of a coactivator protein binding pocket and a hydrophobic ligand binding site (LBS) which are responsible for regulating transcription.	INTRO
96	99	LBS	site	The LBD consists of a coactivator protein binding pocket and a hydrophobic ligand binding site (LBS) which are responsible for regulating transcription.	INTRO
4	30	coactivator binding pocket	site	The coactivator binding pocket of RORγ recognizes a conserved helix motif LXXLL (where X can be any amino acid) on transcriptional coactivator complexes and recruits it to activate transcription.	INTRO
34	38	RORγ	protein	The coactivator binding pocket of RORγ recognizes a conserved helix motif LXXLL (where X can be any amino acid) on transcriptional coactivator complexes and recruits it to activate transcription.	INTRO
52	61	conserved	protein_state	The coactivator binding pocket of RORγ recognizes a conserved helix motif LXXLL (where X can be any amino acid) on transcriptional coactivator complexes and recruits it to activate transcription.	INTRO
62	79	helix motif LXXLL	structure_element	The coactivator binding pocket of RORγ recognizes a conserved helix motif LXXLL (where X can be any amino acid) on transcriptional coactivator complexes and recruits it to activate transcription.	INTRO
11	36	nuclear hormone receptors	protein_type	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
38	42	RORγ	protein	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
45	52	helix12	structure_element	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
89	92	LBD	structure_element	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
121	147	coactivator binding pocket	site	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
183	210	activation function helix 2	structure_element	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
212	215	AF2	structure_element	Like other nuclear hormone receptors, RORγ’s helix12 which makes up the C-termini of the LBD is an essential part of the coactivator binding pocket and is commonly referred to as the activation function helix 2 (AF2).	INTRO
3	7	RORγ	protein	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
33	42	AF2 helix	structure_element	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
64	90	coactivator binding pocket	site	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
108	119	salt bridge	bond_interaction	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
128	134	His479	residue_name_number	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
139	145	Tyr502	residue_name_number	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
161	178	π- π interactions	bond_interaction	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
187	193	Tyr502	residue_name_number	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
198	204	Phe506	residue_name_number	In RORγ, the conformation of the AF2 helix required to form the coactivator binding pocket is mediated by a salt bridge between His479 and Tyr502 in addition to π- π interactions between Tyr502 and Phe506.	INTRO
24	33	AF2 helix	structure_element	The conformation of the AF2 helix can be modulated through targeted ligands which bind the LBS and increase the binding of the coactivator protein (agonists) or disrupt binding (inverse agonists) thereby enhancing or inhibiting transcription.	INTRO
91	94	LBS	site	The conformation of the AF2 helix can be modulated through targeted ligands which bind the LBS and increase the binding of the coactivator protein (agonists) or disrupt binding (inverse agonists) thereby enhancing or inhibiting transcription.	INTRO
6	10	RORγ	protein	Since RORγ has been demonstrated to play an important role in pro-inflammatory gene expression patterns implicated in several major autoimmune diseases, our aim was to develop RORγ inverse agonists that would help down regulate pro-inflammatory gene transcription.	INTRO
176	180	RORγ	protein	Since RORγ has been demonstrated to play an important role in pro-inflammatory gene expression patterns implicated in several major autoimmune diseases, our aim was to develop RORγ inverse agonists that would help down regulate pro-inflammatory gene transcription.	INTRO
0	12	FRET results	evidence	FRET results for agonist BIO592 (a) and Inverse Agonist BIO399 (b)	FIG
17	24	agonist	protein_state	FRET results for agonist BIO592 (a) and Inverse Agonist BIO399 (b)	FIG
25	31	BIO592	chemical	FRET results for agonist BIO592 (a) and Inverse Agonist BIO399 (b)	FIG
40	55	Inverse Agonist	protein_state	FRET results for agonist BIO592 (a) and Inverse Agonist BIO399 (b)	FIG
56	62	BIO399	chemical	FRET results for agonist BIO592 (a) and Inverse Agonist BIO399 (b)	FIG
52	65	benzoxazinone	chemical	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
66	70	RORγ	protein	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
87	94	agonist	protein_state	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
95	101	BIO592	chemical	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
119	134	inverse agonist	protein_state	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
135	141	BIO399	chemical	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
182	239	Fluorescence Resonance Energy transfer (FRET) based assay	experimental_method	Here we present the identification of two synthetic benzoxazinone RORγ ligands, a weak agonist BIO592 (Fig. 1a) and an inverse agonist BIO399 (Fig. 1b) which were identified using a Fluorescence Resonance Energy transfer (FRET) based assay that monitored coactivator peptide recruitment.	INTRO
6	25	partial proteolysis	experimental_method	Using partial proteolysis in combination with mass spectrometry analysis we demonstrate that the AF2 helix of RORγ destabilizes upon BIO399 (inverse agonist) binding.	INTRO
46	63	mass spectrometry	experimental_method	Using partial proteolysis in combination with mass spectrometry analysis we demonstrate that the AF2 helix of RORγ destabilizes upon BIO399 (inverse agonist) binding.	INTRO
97	106	AF2 helix	structure_element	Using partial proteolysis in combination with mass spectrometry analysis we demonstrate that the AF2 helix of RORγ destabilizes upon BIO399 (inverse agonist) binding.	INTRO
110	114	RORγ	protein	Using partial proteolysis in combination with mass spectrometry analysis we demonstrate that the AF2 helix of RORγ destabilizes upon BIO399 (inverse agonist) binding.	INTRO
133	139	BIO399	chemical	Using partial proteolysis in combination with mass spectrometry analysis we demonstrate that the AF2 helix of RORγ destabilizes upon BIO399 (inverse agonist) binding.	INTRO
141	156	inverse agonist	protein_state	Using partial proteolysis in combination with mass spectrometry analysis we demonstrate that the AF2 helix of RORγ destabilizes upon BIO399 (inverse agonist) binding.	INTRO
19	32	binding modes	evidence	Finally, comparing binding modes of our benzoxazinone RORγ crystal structures to other ROR structures, we hypothesize a new mode of action for achieving inverse agonism and selectivity.	INTRO
40	53	benzoxazinone	chemical	Finally, comparing binding modes of our benzoxazinone RORγ crystal structures to other ROR structures, we hypothesize a new mode of action for achieving inverse agonism and selectivity.	INTRO
54	58	RORγ	protein	Finally, comparing binding modes of our benzoxazinone RORγ crystal structures to other ROR structures, we hypothesize a new mode of action for achieving inverse agonism and selectivity.	INTRO
59	77	crystal structures	evidence	Finally, comparing binding modes of our benzoxazinone RORγ crystal structures to other ROR structures, we hypothesize a new mode of action for achieving inverse agonism and selectivity.	INTRO
87	90	ROR	protein_type	Finally, comparing binding modes of our benzoxazinone RORγ crystal structures to other ROR structures, we hypothesize a new mode of action for achieving inverse agonism and selectivity.	INTRO
91	101	structures	evidence	Finally, comparing binding modes of our benzoxazinone RORγ crystal structures to other ROR structures, we hypothesize a new mode of action for achieving inverse agonism and selectivity.	INTRO
8	24	FRET based assay	experimental_method	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
39	46	agonist	protein_state	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
47	53	BIO592	chemical	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
104	111	TRAP220	chemical	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
127	131	RORγ	protein	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
133	137	EC50	evidence	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
150	154	Emax	evidence	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
178	193	inverse agonist	protein_state	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
194	200	BIO399	chemical	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
252	256	IC50	evidence	Using a FRET based assay we discovered agonist BIO592 (Fig. 1a) which increased the coactivator peptide TRAP220 recruitment to RORγ (EC50 0f 58nM and Emax of 130 %) and a potent inverse agonist BIO399 (Fig. 1b) which inhibited coactivator recruitment (IC50: 4.7nM).	RESULTS
53	60	agonist	protein_state	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
61	67	BIO592	chemical	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
72	87	inverse agonist	protein_state	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
88	94	BIO399	chemical	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
115	150	2,3-dihydrobenzo[1,4]oxazepin-4-one	chemical	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
166	172	BIO399	chemical	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
203	226	benzo[1,4]oxazine-3-one	chemical	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
242	248	BIO592	chemical	Interestingly, the structural difference between the agonist BIO592 and inverse agonist BIO399 was minor; with the 2,3-dihydrobenzo[1,4]oxazepin-4-one ring system of BIO399 being 3 atoms larger than the benzo[1,4]oxazine-3-one ring system of BIO592.	RESULTS
152	158	BIO592	chemical	In order to understand how small changes in the core ring system leads to inverse agonism, we wanted to structurally determine the binding mode of both BIO592 and BIO399 in the LBS of RORγ using x-ray crystallography.	RESULTS
163	169	BIO399	chemical	In order to understand how small changes in the core ring system leads to inverse agonism, we wanted to structurally determine the binding mode of both BIO592 and BIO399 in the LBS of RORγ using x-ray crystallography.	RESULTS
177	180	LBS	site	In order to understand how small changes in the core ring system leads to inverse agonism, we wanted to structurally determine the binding mode of both BIO592 and BIO399 in the LBS of RORγ using x-ray crystallography.	RESULTS
184	188	RORγ	protein	In order to understand how small changes in the core ring system leads to inverse agonism, we wanted to structurally determine the binding mode of both BIO592 and BIO399 in the LBS of RORγ using x-ray crystallography.	RESULTS
195	216	x-ray crystallography	experimental_method	In order to understand how small changes in the core ring system leads to inverse agonism, we wanted to structurally determine the binding mode of both BIO592 and BIO399 in the LBS of RORγ using x-ray crystallography.	RESULTS
0	9	Structure	evidence	Structure of the RORγ518-BIO592-EBI96 ternary complex is in a transcriptionally active conformation	RESULTS
17	37	RORγ518-BIO592-EBI96	complex_assembly	Structure of the RORγ518-BIO592-EBI96 ternary complex is in a transcriptionally active conformation	RESULTS
80	86	active	protein_state	Structure of the RORγ518-BIO592-EBI96 ternary complex is in a transcriptionally active conformation	RESULTS
7	24	ternary structure	evidence	 a The ternary structure of RORγ518 BIO592 and EBI96.	FIG
28	35	RORγ518	protein	 a The ternary structure of RORγ518 BIO592 and EBI96.	FIG
36	42	BIO592	chemical	 a The ternary structure of RORγ518 BIO592 and EBI96.	FIG
47	52	EBI96	chemical	 a The ternary structure of RORγ518 BIO592 and EBI96.	FIG
2	6	RORγ	protein	b RORγ AF2 helix in the agonist conformation.	FIG
7	16	AF2 helix	structure_element	b RORγ AF2 helix in the agonist conformation.	FIG
24	31	agonist	protein_state	b RORγ AF2 helix in the agonist conformation.	FIG
2	7	EBI96	chemical	c EBI96 coactivator peptide bound in the coactivator pocket of RORγ	FIG
28	36	bound in	protein_state	c EBI96 coactivator peptide bound in the coactivator pocket of RORγ	FIG
41	59	coactivator pocket	site	c EBI96 coactivator peptide bound in the coactivator pocket of RORγ	FIG
63	67	RORγ	protein	c EBI96 coactivator peptide bound in the coactivator pocket of RORγ	FIG
0	7	RORγ518	protein	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
8	16	bound to	protein_state	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
17	24	agonist	protein_state	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
25	31	BIO592	chemical	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
36	48	crystallized	experimental_method	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
56	65	truncated	protein_state	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
98	103	EBI96	chemical	RORγ518 bound to agonist BIO592 was crystallized with a truncated form of the coactivator peptide EBI96 to a resolution of 2.6 Å (Fig. 2a).	RESULTS
4	13	structure	evidence	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
67	70	ROR	protein_type	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
71	78	agonist	protein_state	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
91	101	structures	evidence	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
107	131	transcriptionally active	protein_state	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
132	164	canonical three layer helix fold	protein_state	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
174	183	AF2 helix	structure_element	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
191	198	agonist	protein_state	The structure of the ternary complex had features similar to other ROR agonist coactivator structures in a transcriptionally active canonical three layer helix fold with the AF2 helix in the agonist conformation.	RESULTS
4	11	agonist	protein_state	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
44	57	hydrogen bond	bond_interaction	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
66	72	His479	residue_name_number	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
77	83	Tyr502	residue_name_number	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
100	116	π-π interactions	bond_interaction	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
125	131	His479	residue_name_number	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
133	139	Tyr502	residue_name_number	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
144	150	Phe506	residue_name_number	The agonist conformation is stabilized by a hydrogen bond between His479 and Tyr502, in addition to π-π interactions between His479, Tyr502 and Phe506 (Fig. 2b).	RESULTS
4	17	hydrogen bond	bond_interaction	The hydrogen bond between His479 and Tyr502 has been reported to be critical for RORγ agonist activity.	RESULTS
26	32	His479	residue_name_number	The hydrogen bond between His479 and Tyr502 has been reported to be critical for RORγ agonist activity.	RESULTS
37	43	Tyr502	residue_name_number	The hydrogen bond between His479 and Tyr502 has been reported to be critical for RORγ agonist activity.	RESULTS
81	85	RORγ	protein	The hydrogen bond between His479 and Tyr502 has been reported to be critical for RORγ agonist activity.	RESULTS
86	93	agonist	protein_state	The hydrogen bond between His479 and Tyr502 has been reported to be critical for RORγ agonist activity.	RESULTS
36	47	mutagenesis	experimental_method	Disrupting this interaction through mutagenesis reduced transcriptional activity of RORγ.	RESULTS
84	88	RORγ	protein	Disrupting this interaction through mutagenesis reduced transcriptional activity of RORγ.	RESULTS
82	91	AF2 helix	structure_element	This reduced transcriptional activity has been attributed to the inability of the AF2 helix to complete the formation of the coactivator binding pocket necessary for coactivator proteins to bind.	RESULTS
125	151	coactivator binding pocket	site	This reduced transcriptional activity has been attributed to the inability of the AF2 helix to complete the formation of the coactivator binding pocket necessary for coactivator proteins to bind.	RESULTS
0	16	Electron density	evidence	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
45	50	EBI96	chemical	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
77	87	EFPYLLSLLG	structure_element	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
103	110	α-helix	structure_element	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
130	154	hydrophobic interactions	bond_interaction	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
164	190	coactivator binding pocket	site	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
194	198	RORγ	protein	Electron density for the coactivator peptide EBI96 was observed for residues EFPYLLSLLG which formed a α-helix stabilized through hydrophobic interactions with the coactivator binding pocket on RORγ (Fig. 2c).	RESULTS
49	58	conserved	protein_state	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
59	72	charged clamp	structure_element	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
103	107	Tyr7	residue_name_number	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
124	129	Leu11	residue_name_number	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
133	138	EBI96	chemical	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
144	158	hydrogen bonds	bond_interaction	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
164	170	Glu504	residue_name_number	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
172	179	helix12	structure_element	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
185	191	Lys336	residue_name_number	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
193	199	helix3	structure_element	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
204	208	RORγ	protein	This interaction is further stabilized through a conserved charged clamp wherein the backbone amide of Tyr7 and carbonyl of Leu11 of EBI96 form hydrogen bonds with Glu504 (helix12) and Lys336 (helix3) of RORγ.	RESULTS
18	31	charged clamp	structure_element	Formation of this charged clamp is essential for RORγ’s function for playing a role in transcriptional activation and this has been corroborated through mutagenic studies in this region.	RESULTS
49	53	RORγ	protein	Formation of this charged clamp is essential for RORγ’s function for playing a role in transcriptional activation and this has been corroborated through mutagenic studies in this region.	RESULTS
153	170	mutagenic studies	experimental_method	Formation of this charged clamp is essential for RORγ’s function for playing a role in transcriptional activation and this has been corroborated through mutagenic studies in this region.	RESULTS
0	6	BIO592	chemical	BIO592 binds in a collapsed conformation stabilizing the agonist conformation of RORγ	RESULTS
18	27	collapsed	protein_state	BIO592 binds in a collapsed conformation stabilizing the agonist conformation of RORγ	RESULTS
57	64	agonist	protein_state	BIO592 binds in a collapsed conformation stabilizing the agonist conformation of RORγ	RESULTS
81	85	RORγ	protein	BIO592 binds in a collapsed conformation stabilizing the agonist conformation of RORγ	RESULTS
29	36	agonist	protein_state	 a Collapsed binding mode of agonist BIO592 in the hydrophobic LBS of RORγ.	FIG
37	43	BIO592	chemical	 a Collapsed binding mode of agonist BIO592 in the hydrophobic LBS of RORγ.	FIG
63	66	LBS	site	 a Collapsed binding mode of agonist BIO592 in the hydrophobic LBS of RORγ.	FIG
70	74	RORγ	protein	 a Collapsed binding mode of agonist BIO592 in the hydrophobic LBS of RORγ.	FIG
2	15	Benzoxazinone	chemical	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
31	38	agonist	protein_state	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
39	45	BIO592	chemical	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
62	68	His479	residue_name_number	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
72	76	RORγ	protein	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
89	96	agonist	protein_state	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
117	126	AF2 helix	structure_element	b Benzoxazinone ring system of agonist BIO592 packing against His479 of RORγ stabilizing agonist conformation of the AF2 helix	FIG
0	6	BIO592	chemical	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
7	15	bound in	protein_state	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
18	27	collapsed	protein_state	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
56	59	LBS	site	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
63	67	RORγ	protein	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
77	83	xylene	chemical	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
121	127	pocket	site	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
135	159	hydrophobic interactions	bond_interaction	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
165	171	Val376	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
173	179	Phe378	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
181	187	Phe388	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
192	198	Phe401	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
209	228	ethyl-benzoxazinone	chemical	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
249	273	hydrophobic interactions	bond_interaction	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
279	285	Trp317	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
287	293	Leu324	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
295	301	Met358	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
303	309	Leu391	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
311	318	Ile 400	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
323	329	His479	residue_name_number	BIO592 bound in a collapsed conformational state in the LBS of RORγ with the xylene ring positioned at the bottom of the pocket making hydrophobic interactions with Val376, Phe378, Phe388 and Phe401, with the ethyl-benzoxazinone ring making several hydrophobic interactions with Trp317, Leu324, Met358, Leu391, Ile 400 and His479 (Fig. 3a, Additional file 3).	RESULTS
4	12	sulfonyl	chemical	The sulfonyl group faces the entrance of the pocket, while the CF3 makes a hydrophobic contact with Ala327.	RESULTS
45	51	pocket	site	The sulfonyl group faces the entrance of the pocket, while the CF3 makes a hydrophobic contact with Ala327.	RESULTS
75	94	hydrophobic contact	bond_interaction	The sulfonyl group faces the entrance of the pocket, while the CF3 makes a hydrophobic contact with Ala327.	RESULTS
100	106	Ala327	residue_name_number	The sulfonyl group faces the entrance of the pocket, while the CF3 makes a hydrophobic contact with Ala327.	RESULTS
0	23	Hydrophobic interaction	bond_interaction	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
55	68	benzoxazinone	chemical	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
73	79	His479	residue_name_number	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
94	100	His479	residue_name_number	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
135	148	hydrogen bond	bond_interaction	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
154	160	Tyr502	residue_name_number	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
185	192	agonist	protein_state	Hydrophobic interaction between the ethyl group of the benzoxazinone and His479 reinforce the His479 sidechain position for making the hydrogen bond with Tyr502 thereby stabilizing the agonist conformation (Fig. 3b).	RESULTS
0	4	RORγ	protein	RORγ AF2 helix is sensitive to proteolysis in the presence of Inverse Agonist BIO399	RESULTS
5	14	AF2 helix	structure_element	RORγ AF2 helix is sensitive to proteolysis in the presence of Inverse Agonist BIO399	RESULTS
50	61	presence of	protein_state	RORγ AF2 helix is sensitive to proteolysis in the presence of Inverse Agonist BIO399	RESULTS
62	77	Inverse Agonist	protein_state	RORγ AF2 helix is sensitive to proteolysis in the presence of Inverse Agonist BIO399	RESULTS
78	84	BIO399	chemical	RORγ AF2 helix is sensitive to proteolysis in the presence of Inverse Agonist BIO399	RESULTS
19	37	co-crystallization	experimental_method	Next, we attempted co-crystallization with the inverse agonist BIO399.	RESULTS
47	62	inverse agonist	protein_state	Next, we attempted co-crystallization with the inverse agonist BIO399.	RESULTS
63	69	BIO399	chemical	Next, we attempted co-crystallization with the inverse agonist BIO399.	RESULTS
19	34	crystallization	experimental_method	However, extensive crystallization efforts with BIO399 and RORγ518 or other AF2 intact constructs did not produce crystals.	RESULTS
48	54	BIO399	chemical	However, extensive crystallization efforts with BIO399 and RORγ518 or other AF2 intact constructs did not produce crystals.	RESULTS
59	66	RORγ518	protein	However, extensive crystallization efforts with BIO399 and RORγ518 or other AF2 intact constructs did not produce crystals.	RESULTS
76	79	AF2	structure_element	However, extensive crystallization efforts with BIO399 and RORγ518 or other AF2 intact constructs did not produce crystals.	RESULTS
80	86	intact	protein_state	However, extensive crystallization efforts with BIO399 and RORγ518 or other AF2 intact constructs did not produce crystals.	RESULTS
114	122	crystals	evidence	However, extensive crystallization efforts with BIO399 and RORγ518 or other AF2 intact constructs did not produce crystals.	RESULTS
25	32	RORγ518	protein	We hypothesized that the RORγ518 coactivator peptide interaction in the FRET assay was disrupted upon BIO399 binding and that a conformational rearrangement of the AF2 helix could have occurred, hindering crystallization.	RESULTS
72	82	FRET assay	experimental_method	We hypothesized that the RORγ518 coactivator peptide interaction in the FRET assay was disrupted upon BIO399 binding and that a conformational rearrangement of the AF2 helix could have occurred, hindering crystallization.	RESULTS
102	108	BIO399	chemical	We hypothesized that the RORγ518 coactivator peptide interaction in the FRET assay was disrupted upon BIO399 binding and that a conformational rearrangement of the AF2 helix could have occurred, hindering crystallization.	RESULTS
164	173	AF2 helix	structure_element	We hypothesized that the RORγ518 coactivator peptide interaction in the FRET assay was disrupted upon BIO399 binding and that a conformational rearrangement of the AF2 helix could have occurred, hindering crystallization.	RESULTS
205	220	crystallization	experimental_method	We hypothesized that the RORγ518 coactivator peptide interaction in the FRET assay was disrupted upon BIO399 binding and that a conformational rearrangement of the AF2 helix could have occurred, hindering crystallization.	RESULTS
34	41	RORγ518	protein	Specific proteolytic positions on RORγ518 when treated with Actinase E alone (Green) or in the presence of BIO399 (Red) and shared proteolytic sites (Yellow)	FIG
47	59	treated with	experimental_method	Specific proteolytic positions on RORγ518 when treated with Actinase E alone (Green) or in the presence of BIO399 (Red) and shared proteolytic sites (Yellow)	FIG
60	70	Actinase E	protein	Specific proteolytic positions on RORγ518 when treated with Actinase E alone (Green) or in the presence of BIO399 (Red) and shared proteolytic sites (Yellow)	FIG
95	106	presence of	protein_state	Specific proteolytic positions on RORγ518 when treated with Actinase E alone (Green) or in the presence of BIO399 (Red) and shared proteolytic sites (Yellow)	FIG
107	113	BIO399	chemical	Specific proteolytic positions on RORγ518 when treated with Actinase E alone (Green) or in the presence of BIO399 (Red) and shared proteolytic sites (Yellow)	FIG
131	148	proteolytic sites	site	Specific proteolytic positions on RORγ518 when treated with Actinase E alone (Green) or in the presence of BIO399 (Red) and shared proteolytic sites (Yellow)	FIG
21	30	AF2 helix	structure_element	The unfolding of the AF2 helix has been observed for other nuclear hormone receptors when bound to an inverse agonist or antagonist.	RESULTS
59	84	nuclear hormone receptors	protein_type	The unfolding of the AF2 helix has been observed for other nuclear hormone receptors when bound to an inverse agonist or antagonist.	RESULTS
90	98	bound to	protein_state	The unfolding of the AF2 helix has been observed for other nuclear hormone receptors when bound to an inverse agonist or antagonist.	RESULTS
102	117	inverse agonist	protein_state	The unfolding of the AF2 helix has been observed for other nuclear hormone receptors when bound to an inverse agonist or antagonist.	RESULTS
8	27	partial proteolysis	experimental_method	We used partial proteolysis in combination with mass spectrometry to determine if BIO399 was causing the AF2 helix to unfold.	RESULTS
48	65	mass spectrometry	experimental_method	We used partial proteolysis in combination with mass spectrometry to determine if BIO399 was causing the AF2 helix to unfold.	RESULTS
82	88	BIO399	chemical	We used partial proteolysis in combination with mass spectrometry to determine if BIO399 was causing the AF2 helix to unfold.	RESULTS
105	114	AF2 helix	structure_element	We used partial proteolysis in combination with mass spectrometry to determine if BIO399 was causing the AF2 helix to unfold.	RESULTS
15	37	Actinase E proteolysis	experimental_method	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
53	60	RORγ518	protein	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
85	92	RORγ518	protein	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
98	105	agonist	protein_state	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
106	112	BIO592	chemical	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
129	134	EBI96	chemical	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
146	157	presence of	protein_state	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
158	173	inverse agonist	protein_state	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
174	180	BIO399	chemical	Results of the Actinase E proteolysis experiments on RORγ518, the ternary complex of RORγ518 with agonist BIO592 and coactivator EBI96, or in the presence of inverse agonist BIO399 supported our hypothesis.	RESULTS
16	37	fragmentation pattern	evidence	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
80	89	AF2 helix	structure_element	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
93	103	Actinase E	protein	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
107	114	RORγ518	protein	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
132	142	504 to 506	residue_range	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
152	167	ternary complex	protein_state	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
205	208	515	residue_number	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
209	212	518	residue_number	Analysis of the fragmentation pattern showed minimal proteolytic removal of the AF2 helix by Actinase E on RORγ518 alone (ending at 504 to 506) and the ternary complex remained primarily intact (ending at 515/518) (Additional file 4).	RESULTS
16	27	presence of	protein_state	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
28	43	inverse agonist	protein_state	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
44	50	BIO399	chemical	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
56	75	proteolytic pattern	evidence	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
178	181	494	residue_number	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
182	185	495	residue_number	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
226	235	AF2 helix	structure_element	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
259	262	APO	protein_state	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
266	289	ternary agonist complex	protein_state	However, in the presence of inverse agonist BIO399, the proteolytic pattern showed significantly less protection, albeit the products were more heterogeneous (majority ending at 494/495), indicating the destabilization of the AF2 helix compared to either the APO or ternary agonist complex (Fig. 4, Additional file 5).	RESULTS
18	35	cocrystallization	experimental_method	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
50	57	RORγ518	protein	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
67	71	RORγ	protein	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
72	81	AF2 helix	structure_element	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
104	118	complexed with	protein_state	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
119	125	BIO399	chemical	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
143	151	crystals	evidence	Several rounds of cocrystallization attempts with RORγ518 or other RORγ AF2 helix containing constructs complexed with BIO399 had not produced crystals.	RESULTS
36	44	crystals	evidence	We attributed the inability to form crystals to the unfolding of the AF2 helix induced by BIO399.	RESULTS
69	78	AF2 helix	structure_element	We attributed the inability to form crystals to the unfolding of the AF2 helix induced by BIO399.	RESULTS
90	96	BIO399	chemical	We attributed the inability to form crystals to the unfolding of the AF2 helix induced by BIO399.	RESULTS
40	48	unfolded	protein_state	We reasoned that if we could remove the unfolded AF2 helix using proteolysis we could produce a binary complex more amenable to crystallization.	RESULTS
49	58	AF2 helix	structure_element	We reasoned that if we could remove the unfolded AF2 helix using proteolysis we could produce a binary complex more amenable to crystallization.	RESULTS
65	76	proteolysis	experimental_method	We reasoned that if we could remove the unfolded AF2 helix using proteolysis we could produce a binary complex more amenable to crystallization.	RESULTS
128	143	crystallization	experimental_method	We reasoned that if we could remove the unfolded AF2 helix using proteolysis we could produce a binary complex more amenable to crystallization.	RESULTS
0	13	AF2 truncated	protein_state	AF2 truncated RORγ BIO399 complex is more amenable to crystallization	RESULTS
14	25	RORγ BIO399	complex_assembly	AF2 truncated RORγ BIO399 complex is more amenable to crystallization	RESULTS
54	69	crystallization	experimental_method	AF2 truncated RORγ BIO399 complex is more amenable to crystallization	RESULTS
14	23	structure	evidence	 a The binary structure of AF2-truncated RORγ and BIO399.	FIG
27	40	AF2-truncated	protein_state	 a The binary structure of AF2-truncated RORγ and BIO399.	FIG
41	45	RORγ	protein	 a The binary structure of AF2-truncated RORγ and BIO399.	FIG
50	56	BIO399	chemical	 a The binary structure of AF2-truncated RORγ and BIO399.	FIG
6	19	superposition	experimental_method	b The superposition of inverse agonist BIO399 (Cyan) and agonist BIO592 (Green).	FIG
23	38	inverse agonist	protein_state	b The superposition of inverse agonist BIO399 (Cyan) and agonist BIO592 (Green).	FIG
39	45	BIO399	chemical	b The superposition of inverse agonist BIO399 (Cyan) and agonist BIO592 (Green).	FIG
57	64	agonist	protein_state	b The superposition of inverse agonist BIO399 (Cyan) and agonist BIO592 (Green).	FIG
65	71	BIO592	chemical	b The superposition of inverse agonist BIO399 (Cyan) and agonist BIO592 (Green).	FIG
14	20	Met358	residue_name_number	c Movement of Met358 and His479 in the BIO399 (Cyan) and BIO592 (Green) structures	FIG
25	31	His479	residue_name_number	c Movement of Met358 and His479 in the BIO399 (Cyan) and BIO592 (Green) structures	FIG
39	45	BIO399	chemical	c Movement of Met358 and His479 in the BIO399 (Cyan) and BIO592 (Green) structures	FIG
57	63	BIO592	chemical	c Movement of Met358 and His479 in the BIO399 (Cyan) and BIO592 (Green) structures	FIG
72	82	structures	evidence	c Movement of Met358 and His479 in the BIO399 (Cyan) and BIO592 (Green) structures	FIG
4	14	Actinase E	protein	The Actinase E treated RORγ518 BIO399 ternary complex (aeRORγ493/4) co-crystallized readily in several PEG based conditions.	RESULTS
23	37	RORγ518 BIO399	complex_assembly	The Actinase E treated RORγ518 BIO399 ternary complex (aeRORγ493/4) co-crystallized readily in several PEG based conditions.	RESULTS
55	66	aeRORγ493/4	complex_assembly	The Actinase E treated RORγ518 BIO399 ternary complex (aeRORγ493/4) co-crystallized readily in several PEG based conditions.	RESULTS
68	83	co-crystallized	experimental_method	The Actinase E treated RORγ518 BIO399 ternary complex (aeRORγ493/4) co-crystallized readily in several PEG based conditions.	RESULTS
4	13	structure	evidence	The structure of aeRORγ493/4 BIO399 complex was solved to 2.3 Å and adopted a similar core fold to the BIO592 agonist crystal structure (Fig. 5a, Additional file 3).	RESULTS
17	35	aeRORγ493/4 BIO399	complex_assembly	The structure of aeRORγ493/4 BIO399 complex was solved to 2.3 Å and adopted a similar core fold to the BIO592 agonist crystal structure (Fig. 5a, Additional file 3).	RESULTS
48	54	solved	experimental_method	The structure of aeRORγ493/4 BIO399 complex was solved to 2.3 Å and adopted a similar core fold to the BIO592 agonist crystal structure (Fig. 5a, Additional file 3).	RESULTS
103	109	BIO592	chemical	The structure of aeRORγ493/4 BIO399 complex was solved to 2.3 Å and adopted a similar core fold to the BIO592 agonist crystal structure (Fig. 5a, Additional file 3).	RESULTS
110	117	agonist	protein_state	The structure of aeRORγ493/4 BIO399 complex was solved to 2.3 Å and adopted a similar core fold to the BIO592 agonist crystal structure (Fig. 5a, Additional file 3).	RESULTS
118	135	crystal structure	evidence	The structure of aeRORγ493/4 BIO399 complex was solved to 2.3 Å and adopted a similar core fold to the BIO592 agonist crystal structure (Fig. 5a, Additional file 3).	RESULTS
4	22	aeRORγ493/4 BIO399	complex_assembly	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
23	32	structure	evidence	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
67	75	Helix 11	structure_element	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
85	105	RORγ518 BIO592 EBI96	complex_assembly	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
106	115	structure	evidence	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
123	131	helix 11	structure_element	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
173	177	L475	residue_name_number	The aeRORγ493/4 BIO399 structure diverged at the c-terminal end of Helix 11 from the RORγ518 BIO592 EBI96 structure, where helix 11 unwinds into a random coil after residue L475.	RESULTS
0	15	Inverse agonist	protein_state	Inverse agonist BIO399 uses Met358 as a trigger for inverse agonism	RESULTS
16	22	BIO399	chemical	Inverse agonist BIO399 uses Met358 as a trigger for inverse agonism	RESULTS
28	34	Met358	residue_name_number	Inverse agonist BIO399 uses Met358 as a trigger for inverse agonism	RESULTS
0	6	BIO399	chemical	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
20	39	ligand binding site	site	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
43	47	RORγ	protein	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
59	68	collapsed	protein_state	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
95	101	BIO592	chemical	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
126	137	superimpose	experimental_method	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
146	150	RMSD	evidence	BIO399 binds to the ligand binding site of RORγ adopting a collapsed conformation as seen with BIO592 where the two compounds superimpose with an RMSD of 0.72 Å (Fig. 5b).	RESULTS
46	52	BIO399	chemical	The majority of the side chains within 4 Å of BIO399 and BIO592 adopt similar rotomer conformations with the exceptions of Met358 and His479 (Fig. 5c).	RESULTS
57	63	BIO592	chemical	The majority of the side chains within 4 Å of BIO399 and BIO592 adopt similar rotomer conformations with the exceptions of Met358 and His479 (Fig. 5c).	RESULTS
123	129	Met358	residue_name_number	The majority of the side chains within 4 Å of BIO399 and BIO592 adopt similar rotomer conformations with the exceptions of Met358 and His479 (Fig. 5c).	RESULTS
134	140	His479	residue_name_number	The majority of the side chains within 4 Å of BIO399 and BIO592 adopt similar rotomer conformations with the exceptions of Met358 and His479 (Fig. 5c).	RESULTS
4	26	difference density map	evidence	The difference density map showed clear positive density for Met358 in an alternate rotomer conformation compared to the one observed in the molecular replacement model or the other agonist containing models (Additional file 6).	RESULTS
40	56	positive density	evidence	The difference density map showed clear positive density for Met358 in an alternate rotomer conformation compared to the one observed in the molecular replacement model or the other agonist containing models (Additional file 6).	RESULTS
61	67	Met358	residue_name_number	The difference density map showed clear positive density for Met358 in an alternate rotomer conformation compared to the one observed in the molecular replacement model or the other agonist containing models (Additional file 6).	RESULTS
141	168	molecular replacement model	experimental_method	The difference density map showed clear positive density for Met358 in an alternate rotomer conformation compared to the one observed in the molecular replacement model or the other agonist containing models (Additional file 6).	RESULTS
182	189	agonist	protein_state	The difference density map showed clear positive density for Met358 in an alternate rotomer conformation compared to the one observed in the molecular replacement model or the other agonist containing models (Additional file 6).	RESULTS
19	25	Met358	residue_name_number	We tried to refine Met358 in the same conformation as the molecular replacement model or the other agonist containing models, but the results clearly indicated that this was not possible, thus confirming the new rotamer conformation for the Met358 sidechain in the inverse agonist bound structure.	RESULTS
58	85	molecular replacement model	experimental_method	We tried to refine Met358 in the same conformation as the molecular replacement model or the other agonist containing models, but the results clearly indicated that this was not possible, thus confirming the new rotamer conformation for the Met358 sidechain in the inverse agonist bound structure.	RESULTS
99	106	agonist	protein_state	We tried to refine Met358 in the same conformation as the molecular replacement model or the other agonist containing models, but the results clearly indicated that this was not possible, thus confirming the new rotamer conformation for the Met358 sidechain in the inverse agonist bound structure.	RESULTS
241	247	Met358	residue_name_number	We tried to refine Met358 in the same conformation as the molecular replacement model or the other agonist containing models, but the results clearly indicated that this was not possible, thus confirming the new rotamer conformation for the Met358 sidechain in the inverse agonist bound structure.	RESULTS
265	286	inverse agonist bound	protein_state	We tried to refine Met358 in the same conformation as the molecular replacement model or the other agonist containing models, but the results clearly indicated that this was not possible, thus confirming the new rotamer conformation for the Met358 sidechain in the inverse agonist bound structure.	RESULTS
287	296	structure	evidence	We tried to refine Met358 in the same conformation as the molecular replacement model or the other agonist containing models, but the results clearly indicated that this was not possible, thus confirming the new rotamer conformation for the Met358 sidechain in the inverse agonist bound structure.	RESULTS
38	44	Met358	residue_name_number	The change in rotomer conformation of Met358 between the agonist and inverse agonist structures is attributed to the gem-dimethyl group on the larger 7 membered benzoxazinone ring system of BIO399.	RESULTS
57	64	agonist	protein_state	The change in rotomer conformation of Met358 between the agonist and inverse agonist structures is attributed to the gem-dimethyl group on the larger 7 membered benzoxazinone ring system of BIO399.	RESULTS
69	84	inverse agonist	protein_state	The change in rotomer conformation of Met358 between the agonist and inverse agonist structures is attributed to the gem-dimethyl group on the larger 7 membered benzoxazinone ring system of BIO399.	RESULTS
85	95	structures	evidence	The change in rotomer conformation of Met358 between the agonist and inverse agonist structures is attributed to the gem-dimethyl group on the larger 7 membered benzoxazinone ring system of BIO399.	RESULTS
161	174	benzoxazinone	chemical	The change in rotomer conformation of Met358 between the agonist and inverse agonist structures is attributed to the gem-dimethyl group on the larger 7 membered benzoxazinone ring system of BIO399.	RESULTS
190	196	BIO399	chemical	The change in rotomer conformation of Met358 between the agonist and inverse agonist structures is attributed to the gem-dimethyl group on the larger 7 membered benzoxazinone ring system of BIO399.	RESULTS
4	14	comparison	experimental_method	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
26	36	structures	evidence	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
52	59	agonist	protein_state	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
89	95	BIO592	chemical	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
96	105	structure	evidence	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
128	134	BIO399	chemical	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
143	149	Met358	residue_name_number	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
155	161	Phe506	residue_name_number	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
169	178	AF2 helix	structure_element	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
195	201	Met358	residue_name_number	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
247	251	RORγ	protein	The comparison of the two structures shows that the agonist conformation observed in the BIO592 structure would be perturbed by BIO399 pushing Met358 into Phe506 of the AF2 helix indicating that Met358 is a trigger for inducing inverse agonism in RORγ (Fig. 5c).	RESULTS
0	6	BIO399	chemical	BIO399 and Inverse agonist T0901317 bind in a collapsed conformation distinct from other RORγ Inverse Agonists Cocrystal structures	RESULTS
11	26	Inverse agonist	protein_state	BIO399 and Inverse agonist T0901317 bind in a collapsed conformation distinct from other RORγ Inverse Agonists Cocrystal structures	RESULTS
27	35	T0901317	chemical	BIO399 and Inverse agonist T0901317 bind in a collapsed conformation distinct from other RORγ Inverse Agonists Cocrystal structures	RESULTS
46	55	collapsed	protein_state	BIO399 and Inverse agonist T0901317 bind in a collapsed conformation distinct from other RORγ Inverse Agonists Cocrystal structures	RESULTS
89	93	RORγ	protein	BIO399 and Inverse agonist T0901317 bind in a collapsed conformation distinct from other RORγ Inverse Agonists Cocrystal structures	RESULTS
111	131	Cocrystal structures	evidence	BIO399 and Inverse agonist T0901317 bind in a collapsed conformation distinct from other RORγ Inverse Agonists Cocrystal structures	RESULTS
3	10	Overlay	experimental_method	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
14	18	RORγ	protein	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
19	29	structures	evidence	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
30	38	bound to	protein_state	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
39	45	BIO596	chemical	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
55	61	BIO399	chemical	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
73	81	T0901317	chemical	 a Overlay of RORγ structures bound to BIO596 (Green), BIO399 (Cyan) and T0901317 (Pink).	FIG
2	9	Overlay	experimental_method	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
13	17	M358	residue_name_number	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
21	25	RORγ	protein	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
26	35	structure	evidence	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
36	42	BIO596	chemical	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
52	58	BIO399	chemical	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
67	74	Digoxin	chemical	b Overlay of M358 in RORγ structure BIO596 (Green), BIO399 (Cyan), Digoxin (Yellow), Compound 2 (Grey), Compound 48 (Salmon) and Compound 4j (Orange)	FIG
4	24	co-crystal structure	evidence	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
28	32	RORγ	protein	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
38	46	T0901317	chemical	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
68	83	inverse agonist	protein_state	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
87	91	RORγ	protein	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
93	97	IC50	evidence	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
112	140	SRC1 displacement FRET assay	experimental_method	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
148	152	IC50	evidence	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
168	178	FRET assay	experimental_method	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
223	232	collapsed	protein_state	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
261	270	structure	evidence	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
274	280	BIO399	chemical	The co-crystal structure of RORγ with T0901317 (PDB code: 4NB6), an inverse agonist of RORγ (IC50 of 54nM in an SRC1 displacement FRET assay and an IC50 of 59nM in our FRET assay (Additional file 7)) shows that it adopts a collapsed conformation similar to the structure of BIO399 described here.	RESULTS
18	29	superimpose	experimental_method	The two compounds superimpose with an RMSD of 0.81 Å (Fig. 6a).	RESULTS
38	42	RMSD	evidence	The two compounds superimpose with an RMSD of 0.81 Å (Fig. 6a).	RESULTS
21	39	hexafluoropropanol	chemical	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
49	57	T0901317	chemical	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
82	98	electron density	evidence	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
140	146	Met358	residue_name_number	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
168	174	Phe506	residue_name_number	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
182	186	RORγ	protein	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
187	193	BIO592	chemical	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
194	201	agonist	protein_state	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
202	211	structure	evidence	The CF3 group on the hexafluoropropanol group of T0901317 was reported to fit the electron density in two conformations one of which pushes Met358 into the vicinity of Phe506 in the RORγ BIO592 agonist structure.	RESULTS
30	36	Met358	residue_name_number	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
67	75	T0901317	chemical	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
76	80	RORγ	protein	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
81	90	structure	evidence	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
105	111	BIO399	chemical	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
209	217	T0901317	chemical	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
230	236	BIO399	chemical	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
244	254	FRET assay	experimental_method	We hypothesize that since the Met358 sidechain conformation in the T0901317 RORγ structure is not in the BIO399 conformation, this difference could account for the 10-fold reduction in the inverse agonism for T0901317 compared to BIO399 in the FRET assay.	RESULTS
0	21	Co-crystal structures	evidence	Co-crystal structures of RORγ have been generated with several potent inverse agonists adopting a linear conformation distinct from the collapsed conformations seen for BIO399 and T090131718.	RESULTS
25	29	RORγ	protein	Co-crystal structures of RORγ have been generated with several potent inverse agonists adopting a linear conformation distinct from the collapsed conformations seen for BIO399 and T090131718.	RESULTS
98	104	linear	protein_state	Co-crystal structures of RORγ have been generated with several potent inverse agonists adopting a linear conformation distinct from the collapsed conformations seen for BIO399 and T090131718.	RESULTS
136	145	collapsed	protein_state	Co-crystal structures of RORγ have been generated with several potent inverse agonists adopting a linear conformation distinct from the collapsed conformations seen for BIO399 and T090131718.	RESULTS
169	175	BIO399	chemical	Co-crystal structures of RORγ have been generated with several potent inverse agonists adopting a linear conformation distinct from the collapsed conformations seen for BIO399 and T090131718.	RESULTS
180	190	T090131718	chemical	Co-crystal structures of RORγ have been generated with several potent inverse agonists adopting a linear conformation distinct from the collapsed conformations seen for BIO399 and T090131718.	RESULTS
4	19	inverse agonist	protein_state	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
84	90	Trp317	residue_name_number	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
105	111	Tyr502	residue_name_number	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
124	139	inverse agonist	protein_state	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
140	156	hydrogen bonding	bond_interaction	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
168	174	His479	residue_name_number	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
208	215	agonist	protein_state	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
232	236	RORγ	protein	The inverse agonist activity for these compounds has been attributed to orientating Trp317 to clash with Tyr502 or a direct inverse agonist hydrogen bonding event with His479, both of which would perturb the agonist conformation of RORγ.	RESULTS
0	6	BIO399	chemical	BIO399 neither orients the sidechain of Trp317 toward Tyr502 nor forms a hydrogen bond with His479 suggesting its mode of action is distinct from linear inverse agonists (Additional file 8).	RESULTS
40	46	Trp317	residue_name_number	BIO399 neither orients the sidechain of Trp317 toward Tyr502 nor forms a hydrogen bond with His479 suggesting its mode of action is distinct from linear inverse agonists (Additional file 8).	RESULTS
54	60	Tyr502	residue_name_number	BIO399 neither orients the sidechain of Trp317 toward Tyr502 nor forms a hydrogen bond with His479 suggesting its mode of action is distinct from linear inverse agonists (Additional file 8).	RESULTS
73	86	hydrogen bond	bond_interaction	BIO399 neither orients the sidechain of Trp317 toward Tyr502 nor forms a hydrogen bond with His479 suggesting its mode of action is distinct from linear inverse agonists (Additional file 8).	RESULTS
92	98	His479	residue_name_number	BIO399 neither orients the sidechain of Trp317 toward Tyr502 nor forms a hydrogen bond with His479 suggesting its mode of action is distinct from linear inverse agonists (Additional file 8).	RESULTS
14	29	inverse agonist	protein_state	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
30	48	crystal structures	evidence	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
67	73	Met358	residue_name_number	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
131	135	RORγ	protein	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
136	143	agonist	protein_state	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
144	154	structures	evidence	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
160	166	BIO592	chemical	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
204	222	hydroxycholesterol	chemical	In the linear inverse agonist crystal structures the side chain of Met358 resides in a similar position as the rotomer observed in RORγ agonist structures with BIO592 described here or as observed in the hydroxycholesterol derivatives and therefore would not trigger inverse agonism with these ligands (Fig. 6b).	RESULTS
0	6	BIO399	chemical	BIO399 shows selectivity for RORγ over RORα and RORβ in a GAL4 Cellular Reporter Assay	RESULTS
29	33	RORγ	protein	BIO399 shows selectivity for RORγ over RORα and RORβ in a GAL4 Cellular Reporter Assay	RESULTS
39	43	RORα	protein	BIO399 shows selectivity for RORγ over RORα and RORβ in a GAL4 Cellular Reporter Assay	RESULTS
48	52	RORβ	protein	BIO399 shows selectivity for RORγ over RORα and RORβ in a GAL4 Cellular Reporter Assay	RESULTS
58	86	GAL4 Cellular Reporter Assay	experimental_method	BIO399 shows selectivity for RORγ over RORα and RORβ in a GAL4 Cellular Reporter Assay	RESULTS
0	15	GAL4 cell assay	experimental_method	GAL4 cell assay selectivity profile for BIO399 toward RORα and RORβ in GAL4	TABLE
40	46	BIO399	chemical	GAL4 cell assay selectivity profile for BIO399 toward RORα and RORβ in GAL4	TABLE
54	58	RORα	protein	GAL4 cell assay selectivity profile for BIO399 toward RORα and RORβ in GAL4	TABLE
63	67	RORβ	protein	GAL4 cell assay selectivity profile for BIO399 toward RORα and RORβ in GAL4	TABLE
71	75	GAL4	protein	GAL4 cell assay selectivity profile for BIO399 toward RORα and RORβ in GAL4	TABLE
3	10	Overlay	experimental_method	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
14	18	RORα	protein	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
29	30	β	protein	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
42	43	γ	protein	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
85	91	Met358	residue_name_number	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
144	157	benzoxazinone	chemical	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
173	179	BIO399	chemical	 a Overlay of RORα (yellow), β (pink) and γ (cyan) showing side chain differences at Met358 inverse agonism trigger position and (b) around the benzoxazinone ring system of BIO399	FIG
54	60	BIO399	chemical	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
63	86	cellular reporter assay	experimental_method	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
113	135	ligand binding domains	structure_element	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
139	142	ROR	protein_type	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
143	144	α	protein	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
146	147	β	protein	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
152	153	γ	protein	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
159	167	fused to	experimental_method	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
172	190	DNA binding domain	structure_element	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
198	220	transcriptional factor	protein_type	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
221	225	GAL4	protein	In order to assess the in vivo selectivity profile of BIO399 a cellular reporter assay was implemented where the ligand binding domains of ROR α, β and γ were fused to the DNA binding domain of the transcriptional factor GAL4.	RESULTS
4	7	ROR	protein_type	The ROR-GAL4 fusion proteins were expressed in cells with the luciferase reporter gene under the control of a GAL4 promoter.	RESULTS
8	12	GAL4	protein	The ROR-GAL4 fusion proteins were expressed in cells with the luciferase reporter gene under the control of a GAL4 promoter.	RESULTS
110	114	GAL4	protein	The ROR-GAL4 fusion proteins were expressed in cells with the luciferase reporter gene under the control of a GAL4 promoter.	RESULTS
0	6	BIO399	chemical	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
80	84	RORγ	protein	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
85	89	GAL4	protein	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
113	117	IC50	evidence	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
193	197	GAL4	protein	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
211	214	LBD	structure_element	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
218	221	ROR	protein_type	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
222	223	α	protein	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
227	228	β	protein	BIO399 inhibited the luciferase activity when added to the cells expressing the RORγ-GAL4 fusion with an in vivo IC50 of 42.5nM while showing >235 and 28 fold selectivity over cells expressing GAL4 fused to the LBD of ROR α or β, respectively (Table 1).	RESULTS
4	7	LBS	site	The LBS of RORs share a high degree of similarity.	RESULTS
11	15	RORs	protein_type	The LBS of RORs share a high degree of similarity.	RESULTS
40	46	BIO399	chemical	However, the inverse agonism trigger of BIO399, residue Met358, is a leucine in both RORα and β.	RESULTS
56	62	Met358	residue_name_number	However, the inverse agonism trigger of BIO399, residue Met358, is a leucine in both RORα and β.	RESULTS
69	76	leucine	residue_name	However, the inverse agonism trigger of BIO399, residue Met358, is a leucine in both RORα and β.	RESULTS
85	89	RORα	protein	However, the inverse agonism trigger of BIO399, residue Met358, is a leucine in both RORα and β.	RESULTS
94	95	β	protein	However, the inverse agonism trigger of BIO399, residue Met358, is a leucine in both RORα and β.	RESULTS
29	35	BIO399	chemical	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
65	72	leucine	residue_name	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
87	91	RORα	protein	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
96	97	β	protein	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
124	137	phenylalanine	residue_name	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
145	154	AF2 helix	structure_element	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
188	194	Met358	residue_name_number	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
212	216	RORγ	protein	This selectivity profile for BIO399 is attributed to the shorter leucine side chain in RORα and β which would not reach the phenylalanine on the AF2 helix further underscoring the role of Met358 as a trigger for RORγ specific inverse agonism (Fig. 7a).	RESULTS
13	17	RORα	protein	Furthermore, RORα contains two phenylalanine residues in its LBS whereas RORβ and γ have a leucine in the same position (Fig. 6b).	RESULTS
31	44	phenylalanine	residue_name	Furthermore, RORα contains two phenylalanine residues in its LBS whereas RORβ and γ have a leucine in the same position (Fig. 6b).	RESULTS
61	64	LBS	site	Furthermore, RORα contains two phenylalanine residues in its LBS whereas RORβ and γ have a leucine in the same position (Fig. 6b).	RESULTS
73	77	RORβ	protein	Furthermore, RORα contains two phenylalanine residues in its LBS whereas RORβ and γ have a leucine in the same position (Fig. 6b).	RESULTS
82	83	γ	protein	Furthermore, RORα contains two phenylalanine residues in its LBS whereas RORβ and γ have a leucine in the same position (Fig. 6b).	RESULTS
91	98	leucine	residue_name	Furthermore, RORα contains two phenylalanine residues in its LBS whereas RORβ and γ have a leucine in the same position (Fig. 6b).	RESULTS
28	41	phenylalanine	residue_name	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
58	61	LBS	site	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
65	69	RORα	protein	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
82	104	dihydrobenzoxazepinone	chemical	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
120	126	BIO399	chemical	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
195	199	RORα	protein	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
205	206	β	protein	We hypothesize that the two phenylalanine residues in the LBS of RORα occlude the dihydrobenzoxazepinone ring system of BIO399 from binding it and responsible for the increase in selectivity for RORα over β.	RESULTS
47	60	benzoxazinone	chemical	We have identified a novel series of synthetic benzoxazinone ligands which modulate the transcriptional activity of RORγ in a FRET based assay.	CONCL
116	120	RORγ	protein	We have identified a novel series of synthetic benzoxazinone ligands which modulate the transcriptional activity of RORγ in a FRET based assay.	CONCL
126	142	FRET based assay	experimental_method	We have identified a novel series of synthetic benzoxazinone ligands which modulate the transcriptional activity of RORγ in a FRET based assay.	CONCL
6	25	partial proteolysis	experimental_method	Using partial proteolysis we show a conformational change which destabilizes the AF2 helix of RORγ when the inverse agonist BIO399 binds.	CONCL
81	90	AF2 helix	structure_element	Using partial proteolysis we show a conformational change which destabilizes the AF2 helix of RORγ when the inverse agonist BIO399 binds.	CONCL
94	98	RORγ	protein	Using partial proteolysis we show a conformational change which destabilizes the AF2 helix of RORγ when the inverse agonist BIO399 binds.	CONCL
108	123	inverse agonist	protein_state	Using partial proteolysis we show a conformational change which destabilizes the AF2 helix of RORγ when the inverse agonist BIO399 binds.	CONCL
124	130	BIO399	chemical	Using partial proteolysis we show a conformational change which destabilizes the AF2 helix of RORγ when the inverse agonist BIO399 binds.	CONCL
8	12	RORγ	protein	The two RORγ co-crystal structures reported here show how a small change to the core ring system can modulate the mode of action from agonist (BIO592) to inverse agonism (BIO399).	CONCL
13	34	co-crystal structures	evidence	The two RORγ co-crystal structures reported here show how a small change to the core ring system can modulate the mode of action from agonist (BIO592) to inverse agonism (BIO399).	CONCL
134	141	agonist	protein_state	The two RORγ co-crystal structures reported here show how a small change to the core ring system can modulate the mode of action from agonist (BIO592) to inverse agonism (BIO399).	CONCL
143	149	BIO592	chemical	The two RORγ co-crystal structures reported here show how a small change to the core ring system can modulate the mode of action from agonist (BIO592) to inverse agonism (BIO399).	CONCL
171	177	BIO399	chemical	The two RORγ co-crystal structures reported here show how a small change to the core ring system can modulate the mode of action from agonist (BIO592) to inverse agonism (BIO399).	CONCL
67	71	RORγ	protein	Finally, we are reporting a newly identified trigger for achieving RORγ specific inverse agonism in an in vivo setting through Met358 which perturbs the agonist conformation of the AF2 helix and prevents coactivator protein binding.	CONCL
127	133	Met358	residue_name_number	Finally, we are reporting a newly identified trigger for achieving RORγ specific inverse agonism in an in vivo setting through Met358 which perturbs the agonist conformation of the AF2 helix and prevents coactivator protein binding.	CONCL
153	160	agonist	protein_state	Finally, we are reporting a newly identified trigger for achieving RORγ specific inverse agonism in an in vivo setting through Met358 which perturbs the agonist conformation of the AF2 helix and prevents coactivator protein binding.	CONCL
181	190	AF2 helix	structure_element	Finally, we are reporting a newly identified trigger for achieving RORγ specific inverse agonism in an in vivo setting through Met358 which perturbs the agonist conformation of the AF2 helix and prevents coactivator protein binding.	CONCL