SII-SWORD/CoKE huggingface dataset:
Neuromedin B receptor (NeuroB_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Bombesins are peptide neurotransmitters whose biological activity resides in a common C-terminal sequence, WAXGHXM. In the periphery, bombesin-related peptides stimulate smooth muscle and glandular secretion. In the brain, these peptides are believed to play a role in homeostasis, thermoregulation and metabolism, and have been reported to elicit analgesia and excessive grooming, together with central regulation of a variety of peripheral effects.

Mammalian bombesins are encoded by 2 genes. The preproGRP gene transcript encodes a precursor of 147 amino acids, which gives GRP and GRP18-27. The preproNMB gene transcript encodes a precursor of 117 amino acids, which is metabolised to neuromedin B. Receptors for these peptides have widespread distribution in peripheral tissue. High levels are found in smooth muscle and in the brain.

The neuromedin B receptor has been characterised in rat oesophagus and rat urinary bladder. It is widespread in the CNS, and is found in high levels in olfactory nucleus and thalamic regions, and in lower levels in the frontal cortex, dendate gyrus, amygdala and dorsal raphe. The receptor activates the phosphoinositide pathway through a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
C3a anaphylatoxin chemotactic receptor (Anaphtx_C3AR1)
Type: Family

The activation of the complement cascade produces a number of small fragments that are bioactive: potent chemoattractants and secretagogues that act on immune and non-immune cells . Similar peptides can also be released by the actions of non-complement proteases, for instance during clotting . Initially these were termed anaphylatoxins because of their effect on mast cell histamine release, but were reclassified as complement component peptides. They include C3a and C5a, which are involved immune response , neural development and organ regeneration . A third peptide, C4a, has a similar structure, but it is inactive in humans . Since the primary function of complement component peptides is in inflammation, they are important targets for the development of anti-inflammatory therapies .

The anaphylatoxin chemotactic receptors (also known as complement peptide receptors) are a group of rhodopsin-like G-protein coupled receptors (GPCRs) . There are three subtypes: C3a anaphylatoxin chemotactic receptor (C3AR1) , C5a anaphylatoxin chemotactic receptor (C5AR1) and C5a anaphylatoxin chemotactic receptor C5L2 (C5AR2) . Both C3AR1 and C5AR1 receptors are classical GPCRs. However, C5AR2 appears to be permanently uncoupled from G proteins but can associate with beta-arrestin . Nevertheless, it has been shown that activation of both C5AR1 and C5AR2 is required for a full pro-inflammatory response, particularly in mice . Several receptor antagonists have been reported , although none, so far, have been show to be effective in humans.

This entry represents C3AR1, also known as complement component 3a receptor 1 and C3aR . It appears to be widely expressed in different lymphoid tissues, providing evidence for a central role in inflammatory processes . This receptor stimulates chemotaxis , granule enzyme release and increases phosphorylated-ERK1/2 production . C3AR1 may provide a theraputic avenue for the treatment of asthma , retinal degeneration , and rheumatoid arthritis .
Folylpolyglutamate synthetase (Folylpolyglutamate_synth)
Type: Family

Folylpolyglutamate synthase

(FPGS) is an ATP-dependent enzyme that is responsible for the addition of a polyglutamate tail to folate and folate derivatives . It plays a key role in the retention of the intracellular folate pool. In some bacteria, such as Escherichia coli, the addition of L-glutamate to dihydropteroate (dihydrofolate synthetase activity) and the subsequent additions of L-glutamate to tetrahydrofolate (FPGS activity) are catalyzed by the same enzyme, FolC .

The crystal structure of the MgATP complex of the enzyme from Lactobacillus casei reveals FPGS to be a modular protein, consisting of two domains, one with a typical mononucleotide-binding fold and the other similar to the folate-binding enzyme dihydrofolate reductase. The active site of the enzyme is located in a large interdomain cleft adjacent to an ATP-binding P-loop motif. Opposite this site, in the C domain, a cavity likely to be the folate binding site has been identified, and inspection of this cavity and the surrounding protein structure suggests that the glutamate tail of the substrate may project into the active site. A further feature of the structure is a well defined ω-loop, which contributes both to the active site and to interdomain interactions .
Pentapeptide repeat (5peptide_repeat)
Type: Repeat

These repeats were first identified in many cyanobacterial proteins but they are now found ubiquitously in all kingdoms of life . The repeats were first identified in hglK . Pentapeptide repeat proteins (PRPs) are characterised by the repetition of the pentapeptide repeat motif [S,T,A,V][D,N][L,F][S,T,R][G], which allows it to adopt a right-handed β-helical structure conformation . The functions of these repeats is unknown but it has been shown that members of this family share the ability to interact with DNA-binding proteins, such as DNA gyrase. For example, McbG (from Escherichia coli) protects the DNA gyrase from microcin B17 toxicity, MfpAMt (from Mycobacterium tuberculosis) and Qnr (from Klebsiella pneumoniae and other enterobacteria) are involved in resistance to fluoroquinolones .

The structures of several members of the pentapeptide repeat-containing family were determined . The structure of MfpA represents a form of DNA mimicry as it exhibits size, shape, and electrostatic similarity to B-form DNA and thus acting as a DNA gyrase inhibitor .
DNA-binding HTH domain, TetR-type (HTH_TetR)
Type: Domain

This entry represents a DNA-binding domain with a helix-turn-helix (HTH) structure that is found in several bacterial and archaeal transcriptional regulators, such as TetR, the tetracycline resistance repressor. Numerous other transcriptional regulatory proteins also contain HTH-type DNA-binding domains, and can be grouped into subfamilies based on sequence similarity. The domain represented by this entry is found in a subfamily of proteins that includes the transcriptional regulators TetR, TetC, AcrR, BetI, Bm3R1, EnvR, QacR, MtrR, TcmR, Ttk, YbiH, and YhgD . Many of these proteins function as repressors that control the level of susceptibility to hydrophobic antibiotics and detergents. They all have similar molecular weights, ranging from 21 to 25kDa. The helix-turn-helix motif is located in the initial third of the protein. The 3D structure of the homodimeric TetR protein complexed with 7-chloro-tetracycline-magnesium has been determined to 2.1 A resolution . TetR folds into ten α-helices with connecting turns and loops. The three N-terminal α-helices of the repressor form the DNA-binding domain: this structural motif encompasses an HTH fold with an inverse orientation compared with that of other DNA-binding proteins.
Helicase, C-terminal domain-like (Helicase_C-like)
Type: Domain

Helicases have been classified in 5 superfamilies (SF1-SF5). For the two largest groups, commonly referred to as SF1 and SF2, a total of seven characteristic motifs has been identified . These two superfamilies encompass a large number of DNA and RNA helicases from archaea, eubacteria, eukaryotes and viruses.

This entry represents the C-terminal domain found in proteins belonging to the helicase superfamilies 1 and 2. Included in this group is the eukaryotic translation initiation factor 4A (eIF4A), a member of the DEA(D/H)-box RNA helicase family. The structure of the carboxyl-terminal domain of eIF4A has been determined; it has a parallel α-β topology that superimposes, with minor variations, on the structures and conserved motifs of the equivalent domain in other, distantly related helicases .
Gastrin/cholecystokinin peptide hormone (Gastrin/CCK)
Type: Domain

Gastrin and cholecystokinin (CCK) are structurally and functionally related peptide hormones that function as hormonal regulators of various digestive processes and feeding behaviors. They are known to induce gastric secretion, stimulate pancreatic secretion, increase blood circulation and water secretion in the stomach and intestine, and stimulate smooth muscle contraction. Originally found in the gut, these hormones have since been shown to be present in various parts of the nervous system. Like many other active peptides they are synthesized as larger protein precursors that are enzymatically converted to their mature forms. They are found in several molecular forms due to tissue-specific post-translational processing. The biological activity of gastrin and CCK is associated with the last five C-terminal residues. One or two positions downstream, there is a conserved sulphated tyrosine residue. The amphibian caerulein skin peptide, the cockroach leukosulphakinin I and II (LSK) peptides, Drosophila melanogaster (Fruit fly) putative CCK-homologues Drosulphakinins I and II, cionin, a Gallus gallus (Chicken) gastrin/cholecystokinin-like peptide and cionin, a neuropeptide from the protochordate Ciona intestinalis belong to the same family.
Marek's disease glycoprotein A (Marek_A)
Type: Family

Herpesviruses have been implicated as a cause of tumours in a number of species. The common tumour condition of the fowl is caused by Meleagrid herpesvirus 1 (MeHV-1). Although infection is ubiquitous, only a proportion of fowl develop tumours, and the precise details of the process of tumour induction remains to be elucidated. Secretory glycoprotein GP57-65 precursor (glycoprotein A - GA) is thought to play an immunoevasive role in the pathogenesis of Marek's disease. It is a candidate for causing the early-stage immunosuppression that occurs after MDHV infection. The protein is predominantly secreted, but a small amount of mature GP57-65 is anchored in the plasma membrane, or held by other interactions. GA is similar to Herpesvirus glycoprotein C, and belongs to the immunoglobulin gene superfamily .
Neutrophil cytosol factor 1 (P47PHOX)
Type: Family

Phagocytes form the first line of defence against invasion by micro-organisms. Engulfing of bacteria by neutrophils is accompanied by the consumption of large amounts of oxygen - a so-called respiratory burst. Defects in phagocytosis involving the lack of a respiratory burst give rise to chronic granulomatous disease (CGD), in which patients are pre-disposed to infection, often from otherwise non-pathogenic bacteria .

Regulation of the respiratory burst takes place at the phagocytic vacuole. The process is mediated by NADPH oxidase, which transports electrons across the plasma membrane to form superoxide (an oxygen molecule with an extra electron that is toxic to normal cells) in the vacuole interior. The electrons are carried across the membrane by a short electron transport chain in the form of an unusual flavocytochrome b .

To conserve NADPH and avoid the toxic effects of superoxide, the oxidase remains inactive until it receives an appropriate stimulus. Activation involves the participation of a number of cytosolic proteins, some of which attach to the flavocytochrome. p47phox, p67phox and p40phox are specialised components of phagocytic cells, all of which contain SH3 domains, by means of which they attach to proline-rich regions of other proteins. p40phox and p47phox share an additionnal domain, PX (phox). Upon activation, p47phox and p67phox are phosphorylated and, with p40phox, translocate to the region of the plasma membrane forming the phagocytic vacuole, where they associates with hydrophilic regions of the flavocytochrome .

This entry represents p67phox, also known as neutrophil cytosol factor 1.
Pseudouridine synthase, TruD (PsdUridine_synth_TruD)
Type: Family

Pseudouridine synthase TruD modifies uracil-13 in tRNA . TruD belongs to a large family of pseudouridine synthases present in all kingdoms of life . It folds into a V-shaped molecule with an RNA-binding cleft formed between its two domains: a catalytic domain and an insertion domain. The catalytic domain differs in sequence but is structurally very similar to the catalytic domain of other pseudouridine synthases. The insertion (or TRUD) domain displays an α/β structure that forms a compact fold titled away from the catalytic domain to create a deep cleft in TruD which is lined with basic residues from each domain. The insertion domain is characterised by two conserved sequence motifs that form a part of the hydrophobic core, as well as by large insertions at several specific sites that are seen in many archaeal and eukaryotic homologues. The insertion domain is likely to be involved in substrate recognition and may represent a RNA binding module .

Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are :

Pseudouridine synthase I, TruA.

Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.

Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.

Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.

Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.
Hedgehog protein (Hedgehog)
Type: Family

Hedgehog proteins are a family of secreted signal molecules required for embryonic cell differentiation. They are synthesised as inactive precursors with an N-terminal signalling domain linked to a C-terminal autoprocessing domain. The three-dimensional structure of the autolytic domain of the hedgehog protein of shows similarity with the β-strand core of intein splicing domains. It has hence been termed the hint (Hedgehog/Intein) domain .

The activated hedgehog protein is involved in segment polarity and cell to cell communication, and plays important roles in both early embryogenesis and metamorphosis . The protein is expressed in embryo stripes , and in several groups of cells belonging to the foregut, hindgut and various other unidentified tissues. Maximum expression is seen in embryos 6-12 hours after fertilisation, and in pupae 1-24 hours after puparium formation.
Gonadotrophin-releasing hormone receptor family (GphnRH_fam_rcpt)
Type: Family

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone releasing hormone (LHRH) and luliberin, is synthesized and released from neurons within the hypothalamus . GnRH is a regulator of reproductive processes, and is responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, playing an important role in the control of gonadal function and normal ovarian cyclicity .

There are two major forms of receptor for GnRH, termed GnRHR and GnRHR2 , which are members the rhodopsin-like G-protein coupled receptor (GPCR) family. They are expressed on the surface of pituitary gonadotrope cells, as well as lymphocytes, breast, ovary and prostate . GnRHR and GnRHR2 couple primarily to Gq/11 but coupling to Gs and Gi in some systems . In addition, GnRHR2 may mediate G protein-independent signalling to protein kinases .

Gonadotropin-releasing hormone receptors are of potential therapeutic use in the suppression of prostate cancer and endometriosis, as they have been shown to exert antiproliferative and/or proapoptotic effects on hormone-dependent cancer cells and mediate the effects of cytotoxins . They may also have application in a number of sex hormone-dependent conditions .

This entry represents the gonadotrophin releasing hormone receptor family and includes GnRHR and GnRHR2.
Sterile alpha motif domain (SAM)
Type: Domain

The sterile alpha motif (SAM) domain is a protein interaction module present in a wide variety of proteins involved in many biological processes. The SAM domain that spreads over around 70 residues and one of the most common protein modules found in eukaryotic genomes . SAM domains have been shown to form homo- and hetero-oligomers, forming multiple self-association architectures and also binding to various non-SAM domain-containing proteins , nevertheless with a low affinity constant . SAM domains also appear to possess the ability to bind RNA . Smaug, a protein that helps to establish a morphogen gradient in Drosophila embryos by repressing the translation of nanos (nos) mRNA, binds to the 3' untranslated region (UTR) of nos mRNA via two similar hairpin structures. The 3D crystal structure of the Smaug RNA-binding region shows a cluster of positively charged residues on the Smaug-SAM domain, which could be the RNA-binding surface. This electropositive potential is unique among all previously determined SAM-domain structures and is conserved among Smaug-SAM homologues. These results suggest that the SAM domain might have a primary role in RNA binding.

Structural analyses show that the SAM domain is arranged in a small five-helix bundle with two large interfaces . In the case of the SAM domain of EphB2, each of these interfaces is able to form dimers. The presence of these two distinct intermonomers binding surface suggest that SAM could form extended polymeric structures .
Glycoside hydrolase, family 37 (Glyco_hydro_37)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 37

comprises enzymes with only one known activity; trehalase (

).

Trehalase is the enzyme responsible for the degradation of the disaccharide alpha,alpha-trehalose yielding two glucose subunits . It is an enzyme found in a wide variety of organisms and whose sequence has been highly conserved throughout evolution.
Elongation factor 1B gamma, C-terminal (EF1B_G_C)
Type: Domain

Translation elongation factors are responsible for two main processes during protein synthesis on the ribosome . EF1A (or EF-Tu) is responsible for the selection and binding of the cognate aminoacyl-tRNA to the A-site (acceptor site) of the ribosome. EF2 (or EF-G) is responsible for the translocation of the peptidyl-tRNA from the A-site to the P-site (peptidyl-tRNA site) of the ribosome, thereby freeing the A-site for the next aminoacyl-tRNA to bind. Elongation factors are responsible for achieving accuracy of translation and both EF1A and EF2 are remarkably conserved throughout evolution.

Elongation factor EF1B (also known as EF-Ts or EF-1beta/gamma/delta) is a nucleotide exchange factor that is required to regenerate EF1A from its inactive form (EF1A-GDP) to its active form (EF1A-GTP). EF1A is then ready to interact with a new aminoacyl-tRNA to begin the cycle again. EF1B is more complex in eukaryotes than in bacteria, and can consist of three subunits: EF1B-alpha (or EF-1beta), EF1B-gamma (or EF-1gamma) and EF1B-beta (or EF-1delta) .

This entry represents a conserved domain usually found near the C terminus of EF1B-gamma chains, a peptide of 410-440 residues. The gamma chain appears to play a role in anchoring the EF1B complex to the beta and delta chains and to other cellular components.
Aromatic-ring-hydroxylating dioxygenase, alpha subunit (Rng_hydr_dOase-A)
Type: Family

Aromatic ring hydroxylating dioxygenases are multicomponent 1,2-dioxygenase complexes that convert closed-ring structures to non-aromatic cis-diols . The complex has both hydroxylase and electron transfer components. The hydroxylase component is itself composed of two subunits: an alpha-subunit of about 50kDa, and a beta-subunit of about 20kDa. The electron transfer component is either composed of two subunits: a ferredoxin and a ferredoxin reductase or by a single bifunctional ferredoxin/reductase subunit. Sequence analysis of hydroxylase subunits of ring hydroxylating systems (including toluene, benzene and napthalene 1,2-dioxygenases) suggests they are derived from a common ancestor . The alpha-subunit binds both a Rieske-like 2Fe-2S cluster and an iron atom: conserved Cys and His residues in the N-terminal region may provide 2Fe-2S ligands, while conserved His and Tyr residues may coordinate the iron. The beta subunit may be responsible for the substrate specificity of the dioxygenase system .
Phosphatidylinositol transfer protein (PI_transfer)
Type: Family

Phosphatidylinositol transfer proteins (PITPs) are ubiquitous cytosolic proteins that catalyse the transfer of phosphatidylinositol (PI) between membranes . PITPs are an essential component of the polyphosphoinositide synthesis machinery and is hence required for proper signalling by epidermal growth factor and f-Met-Leu-Phe, as well as for exocytosis. The role of PITP in polyphosphoinositide synthesis may also explain its involvement in intracellular vesicular traffic . Phosphatidylinositol transfer protein alpha and beta isoforms (PIPNA/B) are also able to catalyse the transfer of phosphatidylcholine (PC) between membranes . PIPNB is required for COPI-mediated retrograde transport from the Golgi to the endoplasmic reticulum where phosphatidylinositol and phosphatidylcholine transfer activity is essential for this function .
DDH domain (DDH_dom)
Type: Domain

This is a domain of predicted phosphoesterases, including Drosophila prune protein and bacterial RecJ exonuclease . The RecJ protein of Escherichia coli plays an important role in a number of DNA repair and recombination pathways. RecJ catalyses processive degradation of single-stranded DNA in a 5'-to-3' direction. Sequences highly related to those encoding RecJ can be found in many of the eubacterial genomes sequenced to date .