SII-SWORD/CoKE huggingface dataset:
Glucose-dependent insulinotropic receptor (GPR119)
Type: Family

Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. However, recent research has identified certain pharmacological targets that could be investigated to find, for example, new potential cannabinoid receptors or channels . GPR18 , GPR55 , GPR119

show little structural similarity to CB1 and CB2 receptors, but they respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands . However, because they do not fulfill all of the cannabinoid receptor criteria defined by IUPHAR, the classification of these proteins remains a contentious issue due to conflicting pharmacological results. As a result, they remain classified as putative endogenous agonists by IUPHAR .

This entry represents glucose-dependent insulinotropic receptor, also known as G protein-coupled receptor 119. It is expressed predominantly in the pancreas and gastrointestinal tract in rodents and humans, as well as in the brain in rodents . It has been shown to be involved in the control of glucose-dependent insulin release and glucagon-like peptide 1 release, respectively , which caused a reduction in food intake and body weight gain in rats . GPR119 has also been shown to regulate incretin and insulin hormone secretion , behaving as a glucose-dependent insulinotropic receptor. As a result, new drugs acting on the receptor have been suggested as novel treatments for obesity and diabetes . Although GPR119 is phylogenetically related to cannabinoid receptors, only fatty acid amides interact with GPR119 . The potency order is N-oleoyl dopamine >oleoyl ethanolamide >palmitoyl ethanolamide >anandamide . However, because only N-oleoyl dopamine and oleoyl ethanolamide have reasonably high (low micromolar) affinity for GPR119, and because neither of these lipids interacts with CB1 or CB2 receptors, GPR119 cannot currently be viewed as a cannabinoid receptor .
Thiamine transporter 2 (ThTr-2)
Type: Family

Thiamine transporter 2 (ThTr-2, also known as SLC19A3) belongs to the reduced folate carrier (RFC) transporter family (

). However, it has no folate transport activity. It mediates high affinity thiamine uptake, propably via a proton anti-port mechanism .

Mutations in ThTr-2 genes cause the thiamine-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disease characterised by megaloblastic anemia, diabetes mellitus, and sensorineural deafness .
Thiamine transporter 1 (ThTr-1)
Type: Family

Thiamine transporter 1 (ThTr-1, also known as SLC19A2) belongs to the reduced folate carrier (RFC) transporter family (

). However, it has no folate transport activity. It is a high-affinity transporter for the intake of thiamine .

Also included in this group is the folate-like transporter 2 from the nematode Caenorhabditis elegans, which does not appear to act as a folate transporter .
Reduced folate transporter SLC19A1 (SLC19A1)
Type: Family

Reduced folate transporter SLC19A1 (also known as folate transporter 1 or RFC) belongs to the RFC transporter family (

). It is a transporter for the intake of folate, reduced folates and methotrexate . It has a function in folate homeostasis and thus in preventing diseases such as neural tube defects and other birth defects . Mutations in the SLC19A1 gene have been found to be correlated with various cancers and with variable response to methotrexate and related compounds for rheumatoid arthritis and cancer .
E3 ubiquitin-protein ligase Mdm2 (Mdm2)
Type: Family

MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome . p53 acts as an important defense mechanism against cancer, and is negatively regulated by interaction with the oncoprotein MDM2 . MDM2 overexpression correlates with metastasis and advanced forms of several cancers and may be used as a cancer drug target . In addition, MDM2 has important roles in the cell independent of p53. It interacts with several proteins such as Rb/E2F-1 complex , the DNA methyltransferase DNMT3A , p107 , MTBP and the cyclin kinase inhibitor p21 . MDM2 also affects cell apoptosis .
Complement factor B (Complement_B)
Type: Family

This group represents a complement factor B. Factor B is part of the alternate pathway of the complement system. It is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation .
Tetrahydromethanopterin S-methyltransferase subunit H (MtrH)
Type: Family

In archaea the enzyme tetrahydromethanopterin S-methyltransferase is composed of eight subunits, MtrA-H. The enzyme is a membrane- associated enzyme complex which catalyzes an energy-conserving, sodium-ion-translocating step in methanogenesis from hydrogen and carbon dioxide . Subunit MtrH catalyzes the methylation reaction and was shown to exhibit methyltetrahydromethanopterin:cob(I)alamin methyltransferase activity .

CH3-H4MPT + cob(I)alamin -->H4MPT + CH3-cob(III)alamin (H4MPT = tetrahydromethanopterin)
Fructose-1,6-bisphosphatase (FBPtase)
Type: Family

Fructose bisphosphatase (FBPase)

is a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate . It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg
2+
and Mn
2+
being preferred) and the enzyme is potently inhibited by Li
+
. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) . Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism .
Toxin-antitoxin system, toxin component ParE1/4 (ParE1/4)
Type: Family

ParE is encoded from the toxin-antitoxin (TA) gene cassettes parDE, which is widely distributed across bacteria, archaea and bacteriophage. Several parDE operons have been detected in bacteria such as Caulobacter crescentus . This entry represents toxins ParE1 and ParE4.

ParE shares protein sequence homology with RelE, but has different function. ParE is involved in plasmid partition and acts by inhibiting DNA gyrase, converting supercoiled plasmid DNA into a singly cleaved linear form in an ATP-dependent fashion . ParE1 functions to inhibit cell division but not cell growth. The residues at its C terminus are critical for its stability and toxicity .
Aminoglycoside 3-N-acetyltransferase-like (Antibiotic_NAT-like)
Type: Homologous_superfamily

This α/β/α domain is found in aminoglycoside 3-N-acetyltransferases, an enzyme that can use a range of antibiotics with 2-deoxystreptamine rings as acceptor for its acetyltransferase activity, inactivating them. It confers resistance to gentamicin, kanamycin, tobramycin, neomycin and apramycin amongst others . This domain is also found in uncharacterised UPF0340 proteins, including TTHA0583 (

) from Thermus thermophilus.
HAUS augmin-like complex subunit 2 (HAUS2)
Type: Family

This entry represents HAUS augmin-like complex subunit 2 from animals (HAUS2) and plants (AUG2) .
START domain-containing protein (START_dom_prot)
Type: Family

Proteins in this family contain the START domain. Their function is not clear.

START (StAR-related lipid-transfer) is a lipid-binding domain in StAR, HD-ZIP and signalling proteins . StAR (Steroidogenic Acute Regulatory protein) is a mitochondrial protein that is synthesised in response to luteinising hormone stimulation . Expression of the protein in the absence of hormone stimulation is sufficient to induce steroid production, suggesting that this protein is required in the acute regulation of steroidogenesis. Representatives of the START domain family have been shown to bind different ligands such as sterols (StAR protein) and phosphatidylcholine (PC-TP). Ligand binding by the START domain can also regulate the activities of other domains that co-occur with the START domain in multidomain proteins such as Rho-gap, the homeodomain, and the thioesterase domain .
FAD dependent protein (FAD-binding_protein)
Type: Family

This entry represents uncharacterised FAD dependent proteins. Their function is not clear.
Protein PafC-like (PafC-like)
Type: Family

Proteins in this entry are part of the pafABC (proteasome accessory factor) operon. PafC does not seem to be involved in pupylation (ubiquitin-like modification by the mycobacterial proteasome) or substrate degradation. It may play a role in resistance to reactive nitrogen intermediates (RNI) . This entry also includes the uncharacterised HTH-type transcriptional regulator YobV from
Bacillus subtilis
.
DNA replication protein DnaC/insertion sequence IstB-like (DNAC/IstB-like)
Type: Family

This group consists of DNA replication protein DnaC and IS21 transposase regulator IstB, which are close paralogues . DnaC interacts with DnaB and form a primosome complex for DNA replication .
Cyclolysin transport protein CyaE (CyaE)
Type: Family

CyaE belongs to the outer membrane factor (OMF) family, which forms complexes with the cytoplasmic membrane transporters that transport (export) of various solutes (heavy metal cations; drugs, oligosaccharides, proteins, etc.) across the two envelopes of the Gram-negative bacterial cell envelope in a single energy-coupled step . CyaE, together with CyaB and CyaD, is necessary for transport of calmodulin-sensitive adenylate cyclase-hemolysin (cyclolysin) .
Protozoan surface antigen, SAG1 family (Surface_antig_SAG1)
Type: Family

Apicomplexan protozoan parasites like Toxoplasma gondii utilise a variety of secretory and antigenic proteins to invade a host and gain access to the intracellular environment . Most of these proteins belong to the SAG1 family , a group of molecules sharing sequence and structural similarity with the immunodominant surface antigen of T. gondii SAG1 (or P30).
Dihydroxyacetone phosphate acyltransferase (DHAPAT)
Type: Family

Dihydroxyacetonephosphate acyltransferase (DHAPAT) catalyses the first step in the biosynthesis of ether phospholipid plasmalogen, and may play also a significant role in nonether glycerolipid biosynthesis . In humans, mutations in DHAPAT results in the genetic disorder rhizomelic chondrodysplasia punctata type 2, characterised by rhizomelic shortening of femur and humerus, cataract,and severe mental retardation .
Glycerol-3-phosphate acyltransferase, PlsB (GPAT_PlsB)
Type: Family

This entry represents glycerol-3-phosphate acyltransferase (GPAT, also known as glycerol-3-phosphate O-acyltransferase) (

), which is involved in CDP-diacylglycerol biosynthesis.

This entry includes PlsB from E-coli. In many bacteria, PlsB is not found, and appears to be replaced by a two enzyme system for 1-acyl-glycerol-3-phosphate biosynthesis, the PlsX/Y system

.

In humans, there are two isoforms of GPAT, one located in the mitochondrial outer membrane and the other in the endoplasmic reticulum . This entry includes the mitochondrial isoform, GPAT1.
Estrogen receptor beta/gamma (ER-beta/gamma)
Type: Family

There are three distinct estrogen receptor (ER) subtypes: ER-alpha, ER-beta, and a third type (ER-gamma) identified in teleost fish . This entry represents the subtypes beta and gamma.

ER-beta binds estrogens and activates expression of reporter genes containing estrogen response element (ERE). ER-beta differs from ER-alpha in its ligand binding affinities to both natural and synthetic estrogens, tissue distributions, and transactivation properties . The presence of different ER explains the seemingly contradictory actions of estrogens in certain target tissues, and illustrates the complexity of estrogenic action.

.
UDP-glucose 6-dehydrogenase, eukaryotic type (UDPglc_DH_euk)
Type: Family

UDP-glucose 6-dehydrogenase is involved in the biosynthesis of UDP-glucuronic acid (UDP-GlcA), a critical precursor for glycan synthesis. In vertebrates it is involved in the biosynthesis of matrix glycosaminoglycans (hyaluronan, chondroitin sulfate, and heparan sulfan) which play significant roles in signaling, inflammation, morphogenesis, cancer growth and matrix organisation . In plants, it provides nucleotide sugars for cell-wall polymers . Proteins in this entry include human UDP-glucose 6-dehydrogenase .

This entry represents the UDP-glucose 6-dehydrogenase mainly from eukaryotes. However, subsets of bacterial proteins can be found in this entry. Most of the bacterial type of the UDP-glucose 6-dehydrogenase can be found in

.
UDP-glucose 6-dehydrogenase, bacterial type (UDPglc_DH_bac)
Type: Family

UDP-glucose 6-dehydrogenase is involved in the biosynthesis of UDP-glucuronic acid (UDP-GlcA), a critical precursor for glycan synthesis. This process is required for capsule synthesis in some bacteria . This entry represents bacterial type of the UDP-glucose 6-dehydrogenases. However, some non-bacterial proteins can also be found in this entry. This entry does not contain human UDP-glucose 6-dehydrogenase, which can be found in the eukaryotic type of the UDP-glucose 6-dehydrogenase (

).
GDP-mannose 6-dehydrogenase (GDPman_DH)
Type: Family

GDP-mannose 6-dehydrogenase catalyses the oxidation of guanosine diphospho-D-mannose (GDP-D-mannose) to GDP-D-mannuronic acid, a precursor for alginate polymerisation. The alginate layer is essential for cyst or protective biofilm formation in some bacteria .
UDP-N-acetyl-D-mannosamine/glucosamine dehydrogenase (UDP_ManNAc/GlcNAc_DH)
Type: Family

This group includes nucleotide sugar dehydrogenases UDP-N-acetyl-D-mannosamine dehydrogenase , UDP-N-acetyl-D-galactosaminuronic acid dehydrogenase and UDP-N-acetyl-D-glucosamine 6-dehydrogenase . These enzymes participate in acetamido sugar biosynthesis.
GPI-anchor transamidase (GPI_transamidase)
Type: Family

Many glycoproteins of lower and higher eukaryotes are attached to the plasma membrane by means of a glycosylphosphatidylinositol (GPI) anchor, which is added onto newly synthesized proteins in the endoplasmic reticulum (ER). Precursors of GPI anchored proteins have a GPI anchoring signal at their C terminus;
GPI-anchor transamidase (MEROPS identifier C13.005) removes the C-terminal peptide and replaces it with the preformed GPI .
Alginate O-acetyltransferase AlgI (AlgI)
Type: Family

Alginate biosynthesis protein AlgI is a probable poly(beta-D-mannuronate) O-acetylase. Together with AlgJ and AlgF, it forms an inner membrane complex which probably interacts with the alginate polymerisation-transport complex and adds acetyl groups at the O-2 and O-3 positions of polymannuronic acid. Acetylation of alginate is important for the architecture of biofilms . Alginate is also a major microbial factor in resistance to immune effectors .
DNA-directed RNA polymerase, subunit RPB6 (RPB6)
Type: Family

Subunit RPB6/RPABC2 is a common component of eukaryotic RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, respectively. In RNA polymerase II (Pol II), RPB6/RPABC2 is part of the clamp element and together with parts of RPB1 and RPB2 forms a pocket to which the RPB4-RPB7 subcomplex binds .

In addition to RNA polymerases I, II, and III, the essential RNA polymerases present in all eukaryotes, plants have two additional nuclear RNA polymerases, abbreviated as Pol IV and Pol V, that play nonredundant roles in siRNA-directed DNA methylation and gene silencing. Pol IV and Pol V are composed of subunits that are paralogous or identical to the 12 subunits of Pol II, including subunit RPB6 .
Ribosomal protein uL1/ribosomal biogenesis protein (Ribosomal_uL1/biogenesis)
Type: Family

Ribosomal protein uL1 is the largest protein from the large ribosomal subunit. The uL1 protein contains two domains: 2-layer α/β domain and a 3-layer α/β domain (interrupts the first domain). The two domains cycle between open and closed conformations via a hinge motion. In Escherichia coli, uL1 is known to bind to the 23S rRNA. The RNA-binding site of uL1 is highly conserved, with both mRNA and rRNA binding the same binding site. Like several other large ribosomal subunit proteins, uL1 displays RNA chaperone activity . It belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups:

Eubacterial uL1

Algal and plant chloroplast uL1

Cyanelle uL1

Archaebacterial uL1

Vertebrate L10A

Yeast Utp30, Rpl1a, Rpl1b and Mrpl1.

This entry also matches ribosome biogenesis proteins, such as Cic1, which associates with the proteasome and is required for the degradation of specific substrates , and for the synthesis of 60S ribosome subunits .
PhoU (PhoU)
Type: Family

PhoU is a negative regulator in Pho regulon which plays a key role in phosphate homeostasis . Members of the Pho regulon include alkaline phosphatase (AP), the PhoB-PhoR proteins and the PstSCAB and PhoU proteins. PhoU is encoded together with proteins of the phosphate-specific transport (Pst) system in the polycistronic pstSCAB-phoU operon. PhoU is essential for the repression of the Pho regulon at high phosphate conditions by a mechanism which is not fully understood. It has been proposed that PhoU may not only control the abundance of the PstSCAB2 transporter through the PhoBR two-component signaling pathway, but also control its activity . PhoU is known to interact with PhoR and PstB, and it may be involved in the formation of a signaling complex at the cytoplasmic membrane that responds to environmental Pi levels .
FadR, C-terminal domain (FadR_C)
Type: Domain

Bacteria regulate membrane fluidity by manipulating the relative levels of saturated and unsaturated fatty acids within the phospholipids of their membrane bilayers. In Escherichia coli, the transcription factor, FadR, functions as a switch that co-ordinately regulates the machinery required for fatty acid beta-oxidation and the expression of a key enzyme in fatty acid biosynthesis. This single repressor controls the transcription of the whole
fad
regulon . Binding of fadR is specifically inhibited by long chain fatty acyl-CoA compounds.

The crystal structure of FadR reveals a two domain dimeric molecule where the N-terminal winged-helix domain binds DNA (

), and the C-terminal domain binds acyl-CoA . The binding of acyl-CoA to the C-terminal domain results in a conformational change that affects the DNA binding affinity of the N-terminal domain .

FadR is a member of the GntR family of bacterial transcription regulators. The DNA-binding domain is well conserved for this family, whereas the C-terminal effector-binding domain (

) is more variable, and is consequently used to define the GntR subfamilies . The FadR group is the largest subgroup, and is characterised by an all-helical C-terminal domain composed of 6 to 7 α helices . This entry represents the C-terminal domain of FadR.
KA1 domain/Ssp2, C-terminal (KA1/Ssp2_C)
Type: Homologous_superfamily

This entry represents the kinase associated domain 1 (KA1) and the C-terminal domain of the SNF1-like protein kinase Ssp2.
Inactive phospholipase C-like protein 2, EF-hand domain (PLCL2_EFh)
Type: Domain

A group of phospholipase C-related, catalytically inactive proteins have been identified as novel inositol 1,4,5-trisphosphate binding proteins with a domain organisation similar to phospholipase C-delta, but lacking the enzymatic activity. These inactive phospholipase C-like (PLCL) proteins consists of at least two types of proteins (PLCL-1 and PLCL2).

Inactive phospholipase C-like protein 1 is an inositol 1,4,5-trisphosphate binding protein with a domain organisation similar to phospholipase C-delta, but lacking the enzymatic activity. It is involved in inositol phospholipid-based intracellular signaling and it is essential for the function of GABA(A) receptors .

Similar to PLCL-1, PLCL-2 may be involved in both inositol 1,4,5-trisphosphate-mediated and gamma-amino butyric acid-related signaling .

This entry represents the EF-hand domain of PLCL-2.
Centromere protein C/Mif2/cnp3 (CENP-C/Mif2/cnp3)
Type: Family

This entry represents mammalian centromere protein C (CENP-C), budding yeast Mif2 and fission yeast centromere protein 3 (cnp3) . They play an important role in assembly of the kinectochore, which is the microtubule-attachment sites that allow chromosome segregation on the mitotic spindle. It binds to the centromere and interacts with histones . In budding yeast, it is phosphorylated by Aurora kinase Ipl1 . In humans, CENP-C is a component of the CENPA-NAC complex, which is at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and MLF1IP/CENPU .
Protection of telomeres protein 1 (POT1)
Type: Family

In most eukaryotes, their chromosome ends are composed of a single stranded overhang that contains GT-rich repeats and are bound by telomerase ribonucleoproteins (RNPs).

This entry represents a group of telomere binding proteins, including the protection of telomeres protein 1 (POT1) from humans/fission yeast/plants, the telomere end binding proteins (TEBP) alpha from the hypotrichous ciliate Oxytricha nova and Cdc13 from Saccharomyces cerevisiae. They are ribonucleoproteins (RNPs) that play an important role in telomere maintenance, but the precise roles played in end protection and telomere length regulation seem to vary considerably between organisms .
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1, catalytic domain (PLC-delta1_cat)
Type: Domain

Phosphoinositide-specific phospholipase C (PI-PLC), also known as 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase, plays a role in the inositol phospholipid signaling by hydrolysing phosphatidylinositol-4,5-bisphosphate to produce the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These cause the increase of intracellular calcium concentration and the activation of protein kinase C (PKC), respectively.

The PLC family in murine or human species is comprised of multiple subtypes. On the basis of their structure, they have been divided into five classes, beta (beta-1, 2, 3 and 4), gamma (gamma-1 and 2), delta (delta-1, 3 and 4), epsilon, zeta, and eta types .

PLC-delta-1 is required for the maintenance of skin homeostasis. It functions as a calcium amplifier within the cell and is essential in trophoblasts for placental development. It is involved in Alzheimer's disease and hypertension. Furthermore, it regulates cell proliferation and cell-cycle progression . Both PLC-delta-1 and PLC-delta-3 are essential in trophoblasts for placental development .

This entry represents the catalytic domain of PLC-delta1, a TIM barrel with two highly conserved regions (X,

, and Y,

) split by a highly degenerate linker sequence .