SII-SWORD/CoKE huggingface dataset:
TAFH/NHR1 (TAFH_NHR1)
Type: Domain

The TAF homology (TAFH) or Nervy homology region 1 (NHR1) domain is a domain of 95-100 amino acids present in eukaryotic proteins of the MTG/ETO family and whereof the core ~75-80 residues occur in TAF proteins. The transcription initiation TFIID complex is composed of TATA binding protein (TBP) and a number of TBP-associated factors (TAFs). The TAFH/NHR1 domain is named after fruit fly TATA-box-associated factor 110 (TAF110), human TAF105 and TAF130, and the fruit fly protein Nervy, which is a homologue of human MTG8/ETO . The human eight twenty-one (ETO, MTG8 or CBFA2T1) and related myeloid transforming gene products MTGR1 and MTG16 as well as the Nervy protein contain the NHR1-4 domains. The NHR1/TAFH domain occurs in the N-terminal part of these proteins, while a MYND-type zinc finger forms the NHR4 domain . The TAFH/NHR1 domain can be involved in protein-protein interactions, e.g in MTG8/ETO with HSP90 and Gfi-1 .
Bacterial exotoxin B (Bacterial_exotoxin_B)
Type: Family

A large group of bacterial exotoxins are referred to as "A/B toxins", essentially because they are formed from two subunits . The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit. Clostridial species are one of the major causes of food poisoning/gastro-intestinal illnesses. They are Gram-positive, spore-forming rods that occur naturally in the soil . Among the toxins produced by certain Clostridium spp. are the binary exotoxins. These proteins consist of two independent polypeptides, which correspond to the A/B subunit moieties. The enzyme component (A) enters the cell through endosomes produced by the oligomeric binding/translocation protein (B), and prevents actin polymerisation through ADP-ribosylation of monomeric G-actin .

Members of the "B" binary toxin family also include the Bacillus anthracis protective antigen (PA) protein , most likely due to a common evolutionary ancestor. B. anthracis, a large Gram-positive spore-forming rod, is the causative agent of anthrax. Its two virulence factors are the poly-D-glutamate polypeptide capsule, and the actual anthrax exotoxin . The toxin comprises three factors: the protective antigen (PA); the oedema factor (EF); and the lethal factor (LF). Each is a thermolabile protein of ~80kDa. PA forms the "B" part of the exotoxin and allows passage of the "A" moiety (consisting of EF and LF) into target cells. PA protein forms the central part of the complete anthrax toxin, and translocates the B moiety into host cells after assembling as a heptamer in the membrane .
Clostridium enterotoxin (Clenterotox)
Type: Family

Clostridial species are one of the major causes of food poisoning/gastro-intestinal illnesses. They are Gram-positive, spore-forming rods that occur naturally in the soil . Among the family are: Clostridium botulinum, which produces one of the most potent toxins in existence; Clostridium tetani, causative agent of tetanus; and Clostridium perfringens, commonly found in wound infections and diarrhoea cases. The use of toxins to damage the host is a method deployed by many bacterial pathogens.

The major virulence factor of C. perfringens is the CPE enterotoxin, which is secreted upon invasion of the host gut, and contributes to food poisoning and other gastrointestinal illnesses . It has a molecular weight of 35.3kDa, and is responsible for the disintegration of tight junctions between endothelial cells in the gut . This mechanism is mediated by host claudins-3 and -4, situated at the tight junctions.

Two more host receptors have been characterised and expressed
in vivo
. Named CPE-R and RVP1, these may be utilised in the passage of Clostridial species through the gut wall, although the regulatory mechanisms have not been elucidated.

This entry also includes HA-70 from Clostridium botulinum C phage. The hemagglutinin (HA) components of the progenitor toxin protects the structural integrity of botulinum neurotoxin. The structure of HA70 from type C and D toxin (HA70/C/D) has been revealed .
Bordetella pertussis toxin A (Borpert_toxA)
Type: Family

A large group of bacterial exotoxins are referred to as "A/B toxins", essentially because they are formed from two subunits . The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit .

Bordetella pertussis is the causative agent of whooping cough, and is a Gram-negative aerobic coccus. Its major virulence factor is the pertussis toxin, an A/B exotoxin that mediates both colonisation and toxaemic stages of the the disease . Recombinant, inactive forms of the 5 subunits that make up the toxin have proven to be good vaccines. The S1 ("A") subunit of pertussis toxin causes the characteristic sound of the "whoop" in whooping cough. It achieves this through ADP-ribosylation of host Gi alpha-units, an adenylate cyclase inhibitor . Uninhibited, this enzyme produces elevated levels of cAMP, leading to increased cell exudate and inflammation in the lungs .

The crystal structure of pertussis toxin has been determined to 2.9A resolution . The catalytic A-subunit (S1) shares structural similarity with other ADP-ribosylating bacterial toxins, although differences in the C-terminal portion explain its unique activation mechanism. Despite its heterogeneous subunit composition, the structure of the cell-binding B-oligomer (S2, S3, two copies of S4, and S5) resembles the symmetrical B-pentamers of the cholera and shiga toxin families, but it interacts differently with the A-subunit and there is virtually no sequence similarity between B-subunits of the different toxins.
Bordetella pertussis toxin B (ToxinB_BORPE)
Type: Family

A large group of bacterial exotoxins are referred to as "A/B toxins", essentially because they are formed from two subunits . The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit .

Bordetella pertussis is the causative agent of whooping cough, and is a Gram-negative aerobic coccus. Its major virulence factor is the pertussis toxin, an A/B exotoxin that mediates both colonisation and toxaemic stages of the the disease . Recombinant, inactive forms of the 5 subunits that make up the toxin have proven to be good vaccines. The S2 and S3 subunits of the toxin form part of the "B" moiety. They are responsible for binding the whole toxin to host cells prior to invasion, and are classed as adhesins . S2 attaches to a host receptor called lactosylceramide. It has also been speculated that the S3 unit may preferentially bind phagocytes.

The crystal structure of pertussis toxin has been determined to 2.9A resolution . The catalytic A-subunit (S1) shares structural similarity with other ADP-ribosylating bacterial toxins, although differences in the C-terminal portion explain its unique activation mechanism. Despite its heterogeneous subunit composition, the structure of the cell-binding B-oligomer (S2, S3, two copies of S4, and S5) resembles the symmetrical B-pentamers of the cholera and shiga toxin families, but it interacts differently with the A-subunit and there is virtually no sequence similarity between B-subunits of the different toxins. Two peripheral domains that are unique to the pertussis toxin B-oligomer share structural similarity with a calcium-dependent eukaryotic lectin, and reveal possible receptor-binding sites.
KID repeat (KID_repeat)
Type: Repeat

This group of proteins contains the KID repeat as found in Borrelia and spirochete Repeat motif-containing proteins including RepA/Rep+, RepU and various Bdr proteins. RepA and related Borrelia proteins have been suggested to play an important genus-wide role in the biology of the Borrelia . Bdr proteins are polymorphic inner membrane proteins produced by most Borrelia species . The bdr genes of encode proteins that form three distinct subfamilies: BdrD, BdrE, and BdrF. bdr orthologues have been appear to be present in all Borrelia species that have been analysed . It is thought that BdrF2 and the other proteins encoded by the operon form an inner-membrane-associated protein complex that may interact with DNA and which may act during transmission or in the early stages of infection .
Methyl-coenzyme M reductase, protein D (Me_CoM_Rdtase_D)
Type: Family

Methyl-coenzyme M reductase (MCR) catalyses the reduction of methyl-coenzyme M (CH3-SCoM) and coenzyme B (HS-CoB) to methane and the corresponding heterosulphide CoM-S-S-CoB (

), the final step in methane biosynthesis. This reaction proceeds under anaerobic conditions by methanogenic Archaea , and requires a nickel-porphinoid prosthetic group, coenzyme F430, which is in the EPR-detectable Ni(I) oxidation state in the active enzyme. Studies on a catalytically inactive enzyme aerobically co-crystallized with coenzyme M displayed a fully occupied coenzyme M-binding site with no alternate conformations. The binding of coenzyme M appears to induce specific conformational changes that suggests a molecular mechanism by which the enzyme ensures that methyl-coenzyme M enters the substrate channel prior to coenzyme B, as required by the active-site geometry .

MCR is a hexamer composed of 2 alpha, 2 beta, and 2 gamma subunits with two identical nickel porphinoid active sites, which form two long active site channels with F430 embedded at the bottom .

Genes encoding the beta (mcrB) and gamma (mcrG) subunits of MCR are separated by two open reading frames coding for two proteins C and D . The function of proteins C and D is unknown. This entry represents protein D.
Transcription regulator GCM domain (Tscrpt_reg_GCM)
Type: Domain

GCM transcription factors are a family of proteins which contain a GCM motif. The GCM motif is a domain that has been identified in proteins belonging to a family of transcriptional regulators involved in fundamental developmental processes which comprise Drosophila melanogaster GCM and its mammalian homologues . In GCM transcription factors the N-terminal moiety contains a DNA-binding domain of 150 residues. Sequence conservation is highest in this GCM domain. In contrast, the C-terminal moiety contains one or two transactivating regions and is only poorly conserved.

The GCM motif has been shown to be a DNA binding domain that recognises preferentially the nonpalindromic octamer 5'-ATGCGGGT-3' . The GCM motif contains many conserved basic amino acid residues, seven cysteine residues, and four histidine residues . The conserved cysteines are involved in shaping the overall conformation of the domain, in the process of DNA binding and in the redox regulation of DNA binding . The GCM domain is a new class of Zn-containing DNA-binding domain with no similarity to any other DNA-binding domain . The GCM domain consists of a large and a small domain tethered together by one of the two Zn ions present in the structure. The large and the small domains comprise five-and three-stranded β-sheets, respectively, with three small helical segments packed against the same side of the two β-sheets. The GCM domain exercises a novel mode of sequence-specific DNA recognition, where the five-stranded β-pleated sheet inserts into the major groove of the DNA. Residues protruding from the edge strand of the β-pleated sheet and the following loop and strand contact the bases and backbone of both DNA strands, providing specificity for its DNA target site.
Ubiquitin interacting motif (UIM_dom)
Type: Conserved_site

The Ubiquitin Interacting Motif (UIM), or 'LALAL-motif', is a stretch of about 20 amino acid residues, which was first described in the 26S proteasome subunit PSD4/RPN-10 that is known to recognise ubiquitin . In addition, the UIM is found, often in tandem or triplet arrays, in a variety of proteins either involved in ubiquitination and ubiquitin metabolism, or known to interact with ubiquitin-like modifiers. Among the UIM proteins are two different subgroups of the UBP (ubiquitin carboxy-terminal hydrolase) family of deubiquitinating enzymes, one F-box protein, one family of HECT-containing ubiquitin-ligases (E3s) from plants, and several proteins containing ubiquitin-associated UBA and/or UBX domains . In most of these proteins, the UIM occurs in multiple copies and in association with other domains such as UBA (

), UBX (

), ENTH, EH (

), VHS (

), SH3 (

), HECT (

), VWFA (

), EF-hand calcium-binding, WD-40 (

), F-box (

), LIM (

), protein kinase (

), ankyrin (

), PX (

), phosphatidylinositol 3- and 4-kinase (

), C2 (

), OTU (

), dnaJ (

), RING-finger (

) or FYVE-finger (

). UIMs have been shown to bind ubiquitin and to serve as a specific targeting signal important for monoubiquitination. Thus, UIMs may have several functions in ubiquitin metabolism each of which may require different numbers of UIMs .
Apelin receptor (Apelin_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 .

The human APJ gene which encodes this receptor was originally cloned in 1993 using a set of primers based on the 7 conserved TM domains. The putative sequence is closest in terms of identity (40-50% in the TM regions) to the angiotensin receptor (AT1); however, angiotensin II shows no affinity for the receptor . It is a receptor for apelin receptor early endogenous ligand (APELA) and apelin (APLN) hormones, which are coupled to G proteins and inhibit adenylate cyclase activity . The mature transcript encodes a preproprotein that yields a 13 amino acid active peptide from the C-terminal end. Apelin has a similar mRNA distribution to angiotensin II and the active peptides share some similarity. It plays a role in regulation of blood vessel formation, blood pressure, heart contractility and heart failure .
Growth hormone secretagogue receptor/motilin receptor (GHS-R/MTLR)
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 .

Growth hormone secretagogue receptor (GHSR) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin . Ghrelin also increases growth hormone (GH) release . The motilin receptor, also known as GPR38, shares significant amino acid sequence identity with GHSR .
Galanin receptor 1 (GAL1_rcpt)
Type: Family

Galanin is involved in a variety of physiological mechanisms and disease states, from appetite and neuroregeneration to seizures and pain . The actions of galanin are mediated through interaction with specific membrane receptors. Three receptor subtypes have been identified; Galanin receptor 1 (GALR1), Galanin receptor 2 (GALR2) and Galanin receptor 3 (GAL3), all of which are rhodopsin-like GPCRs. They differ from one another in terms of their expression patterns, affinity for various peptide analogues and G protein-coupling specificity . In signaling, all can act via the Gi/o class , whilst GAL2 also has Gq/11 as a major signaling route .

This entry represents the galanin receptor 1 subtype, which is expressed at significant levels in regions of the brain and spinal cord including the hypothalamus, amygdala, hippocampus, thalamus and brainstem. It has also been detected throughout the length of the human gastro-intestinal tract . Galanin receptor 1 reduces the concentration of cAMP , opens G protein-coupled, inwardly rectifying K+ channels , and stimulates MAP kinase activity in a manner that is sensitive to pertussis toxin.
Galanin receptor 2 (GAL2_rcpt)
Type: Family

Galanin is involved in a variety of physiological mechanisms and disease states, from appetite and neuroregeneration to seizures and pain . The actions of galanin are mediated through interaction with specific membrane receptors. Three receptor subtypes have been identified; Galanin receptor 1 (GALR1), Galanin receptor 2 (GALR2) and Galanin receptor 3 (GAL3), all of which are rhodopsin-like GPCRs. They differ from one another in terms of their expression patterns, affinity for various peptide analogues and G protein-coupling specificity . In signaling, all can act via the Gi/o class , whilst GAL2 also has Gq/11 as a major signaling route .

This entry represents the galanin receptor 2 subtype, which is expressed abundantly in both central and peripheral systems. In the brain, it has been found in the hypothalamus, amygdala, hippocampus, pyriform cortex, dendate gyrus, mammillary nuclei and cerebellar cortex . Peripheral regions expressing the receptor include the prostate, uterus, ovary, vas deferens, stomach, intestine, dorsal root, pancreas, liver, heart and retina .
Galanin receptor 3 (Galnin_3_rcpt)
Type: Family

Galanin is involved in a variety of physiological mechanisms and disease states, from appetite and neuroregeneration to seizures and pain . The actions of galanin are mediated through interaction with specific membrane receptors. Three receptor subtypes have been identified; Galanin receptor 1 (GALR1), Galanin receptor 2 (GALR2) and Galanin receptor 3 (GAL3), all of which are rhodopsin-like GPCRs. They differ from one another in terms of their expression patterns, affinity for various peptide analogues and G protein-coupling specificity . In signaling, all can act via the Gi/o class , whilst GAL2 also has Gq/11 as a major signaling route .

This entry represents galanin receptor 3 subtype, which is expressed abundantly in the periphery and at lower levels in the CNS. In the brain, the highest levels have been found in the hypothalamus and pituitary . Expression has also been detected in peripheral tissues, including the pancreas, liver, kidney, stomach, adrenal gland, lung and spleen .
G protein-coupled receptor 37 orphan (GPR37_orph)
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 .

Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. GPR37 was isolated from a set of human brain frontal lobe expressed sequence tags. The GPR37 genomic sequence was subsequently mapped to chromosome 7. A putative orthologue, 83% identical to the human form in terms of predicted amino acid sequence, has since been identified in the mouse genome and mapped to chromosome 6. Northern blot analyses revealed a highly expressed 3.8kb mRNA and a less abundant 8kb mRNA in both human and mouse brain. The 3.8kb mRNA was also less abundantly expressed in human liver and placenta, and a further 3kb mRNA was found in mouse testis .