SII-SWORD/CoKE huggingface dataset:
GPCR, family 3, nine cysteines domain superfamily (GPCR_3_9-Cys_sf)
Type: Homologous_superfamily

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 .

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

This entry represents a conserved sequence, found in the extracellular region, that contains several highly-conserved Cys residues that are predicted to form disulphide bridges.
Ribosomal protein eS26 superfamily (Ribosomal_eS26_sf)
Type: Homologous_superfamily

This family represents the small ribosomal subunit protein eS26 (previously known as S26) which is found mainly in eukaryotes and includes mammalian S26 ; Octopus S26 ; Drosophila S26 (DS31) ; plant cytoplasmic S26; and fungal S26 . S26 may be involved in the attachment of eIF3 and poly (U) . Disruption of RPS26, the gene encoding a homologue of ribosomal protein small subunit S26 in yeast (S. cerevisiae), resulted in the formation of micro-colonies, suggesting that it is important for the normal cell growth of S. cerevisiae . This entry also includes uncharacterised archaeal sequences.
Tim21 IMS domain superfamily (Tim21_IMS_sf)
Type: Homologous_superfamily

Tim21 is an essential component of the TIM23 complex, which mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. Tim21 is required to keep the TOM and the TIM23 complexes in close contact. At some point, it is released from the TOM23 complex to allow protein translocation into the mitochondrial matrix .

Tim21 consists of a single transmembrane segment in the inner membrane, and a large intermembrane space (IMS) domain that has been shown to bind to the IMS domain of the outer membrane of the Tom22 receptor . The binding domain of Tim21 consists of a novel mixed α/β fold .
Myoviridae tail sheath stabiliser superfamily (T4-gp15_tss_sf)
Type: Homologous_superfamily

This entry represents the gp15 protein, which is the tail-sheath-stabiliser or tail-terminator protein of T4-like myoviridae phage. It forms a hexamer and attaches to the top of the phage tail stabilising the contractile sheath and forming the interface for binding of the independently assembled head . The gp15 hexamer interacts with the gp3 hexamer and, presumably, with the C-terminal domains of gp18 molecules located in the last ring of the contractile sheath. It also creates the binding site for attachment of the capsid with mutant phage tails lacking gp15 being unable to join the heads. The tail binds to the head via interactions of gp15 with gp14 (or with both gp13 and gp14) since the latter form a complex that seals the portal vertex and creates an attachment site of the independently assembled tail .
Zincin-like metallopeptidase superfamily (Zincin_1_sf)
Type: Homologous_superfamily

This superfamily of proteins has a conserved HEXXH motif, suggesting they are putative peptidases of zincin fold . The structure of this family is a minimal version of the metalloprotease fold (

).
Tail assembly chaperone Gp13-like superfamily (TAC_Gp13-like_sf)
Type: Homologous_superfamily

Tail assembly chaperones (TACs) are required for the morphogenesis of all long-tailed phages. Gp13, a TAC from bacteriophage HK97, is required for tail tube assembly and is thought to be a TAC. The gp13 monomer comprises a single domain consisting of a small three-stranded twisted β-sheet connected to a helical bundle. Gp13 adopts a spiral quaternary structure, similar to other TACs . This superfamily includes gp13 and putative TACs from other Siphovirus.
RIG-I-like receptor, C-terminal domain superfamily (RLR_C_sf)
Type: Homologous_superfamily

Intracellular RIG-I-like receptors (RLRs: retinoic acid-inducible gene I, RIG-I; melanoma differenciation-associated gene 5, MDA-5; and laboratory of genetics and physiology 2, LGP2) recognise viral RNAs as pathogen-associated molecular patterns (PAMPs) and initiate an antiviral immune response. RLRs belong to the superfamily 2 (SF2) helicases or ATPases. Among SF2 ATPases, RIG-I, MDA5, and LGP2 possess a unique domain structure. RIG-I and MDA5 consist of two N-terminal caspase activation and recruitment domains (CARDs), a central SF2 type DECH box ATPase domain (consisting of
two RecA-like helicase domains, Hel1 and Hel2, and an insert domain, Hel2i), and a C-terminal regulatory (CTR) domain. LGP2 lacks the two N-terminal CARDs but contains the DECH box domain, as well as the CTR domain. The CTR domain helps recognise non-self RNAs within the cellular environment. To facilitate the detection of a broad range of non-self RNA
targets, each RLR contains a similar but divergent CTR domain that mediates RLR-specific interactions between bound nucleic acids or neighbouring patterns .

The RLR CTR domain is a globular, slightly flattened domain with a concave and a convex side. It is structurally organised in three leaves consisting of two four-stranded (β1, β2, β9, β10 and β5, β6, β7, β8) and one two-stranded (β3, β4) antiparallel β-sheets. Small helical turns connect the three β-sheets. The two four stranded β-sheets are laterally connected by two protruding loops, each containing two highly conserved cysteine residues. Together, the four thiol groups of these cysteines coordinate a zinc ion .

This superfamily represents the C-terminal regulatory domain of the RIG-I-like receptor.
SAS-6, N-terminal domain superfamily (SAS-6_N_sf)
Type: Homologous_superfamily

Spindle assembly abnormal protein 6 (SAS-6) is the centre of the cartwheel assembly that scaffolds centrioles early in their biogenesis. Structural studies have shown that SAS-6 self-associates in vitro into assemblies that resemble cartwheel centres through the formation of a parallel coiled-coil dimer .

This entry represents the N-terminal domain of the SAS-6 , both in C.elegans and in humans. The N-terminal domain is the region through which the 9 rod-shaped homodimers that SAS-6 forms on oligomerisation interact with each other. Proper functioning of the centriole requires this correct oligomerisation .
Phage-like element PBSX protein XkdN-like superfamily (XkdN-like_sf)
Type: Homologous_superfamily

This entry is represents Phage-like element PBSX protein XkdN from Bacillus subtilis (strain 168) and similar proteins predominantly found in Firmicutes and some tailed bacteriophages. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches. Members of this group of proteins are chaperones involved in phage tail assembly and have been predicted to form a spiral structure .
Beta-1,3-xylanase, CBM31 domain superfamily (Beta-xylanase_CBM31_sf)
Type: Homologous_superfamily

Many glycoside hydrolases are modular proteins composed of catalytic modules appended to one or more non-catalytic carbohydrate-binding modules (CBMs). CBMs bind to a range of polysaccharides that include crystalline cellulose and hemicelluloses such as glucan, xylan, mannan, and glucomannan. The main function of CBMs is to increase the catalytic efficiency of the enzymes against soluble and/or insoluble substrates by bringing the catalytic module into prolonged and intimate contact with its substrate.

This entry represents the family 31 carbohydrate-binding module (CBM31) of beta-1,3-xylanase .

Beta-1,3-xylan is a homopolymer of b-1,3-linked D-xylose and is a polysaccharide peculiar to marine algae. Beta-1,3-xylanase is a beta-1,3-xylan hydrolyzing enzyme .
Sarcosine oxidase subunit delta superfamily (SoxD_sf)
Type: Homologous_superfamily

These sequences represent the delta subunit of a family of known and putative heterotetrameric sarcosine oxidases. Five operons of such oxidases are found in Rhizobium loti (Mesorhizobium loti) and three in Agrobacterium tumefaciens, a high enough copy number to suggest that not all members share the same function. Sarcosine oxidase catalyzes the oxidative demethylation of sarcosine to glycine. The reaction converts tetrahydrofolate to 5,10-methylene-tetrahydrofolate .
Large ribosomal subunit protein eL34, C-terminal domain superfamily (Ribosomal_eL34_C_sf)
Type: Homologous_superfamily

A number of eukaryotic and archaebacterial ribosomal proteins belong to the eL34 superfamily. These include, vertebrate L34, mosquito L31 , plant L34 , yeast putative ribosomal protein YIL052c and archaebacterial L34e.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Recombination endonuclease VII superfamily (Endonuclease_7_sf)
Type: Homologous_superfamily

This superfamily includes Bacteriophage T4 endonuclease VII, Mycobacteriophage D29 gene 59, and other as yet uncharacterised proteins. The T4 endonuclease VII (Endo VII) recognises a broad spectrum of DNA substrates ranging from branched DNAs to single base mismatches. The structure of this enzyme has been resolved and it was found that the monomers form an elongated, intertwined molecular dimer that exibits extreme domain swapping. Two pairs of antiparallel helices which form a novel 'four-helix cross' motif are the major dimerisation elements .
Repressor of RNA polymerase III transcription Maf1 superfamily (Maf1_sf)
Type: Homologous_superfamily

Maf1 is a negative regulator of RNA polymerase III . It inhibits the de novo assembly of TFIIIB onto DNA . Maf1 represses Pol III in response to DNA damage, oxidative stress, growth to stationary phase, treatment with rapamycin or chlorpromazine, and blocking of the secretory pathway . It targets the initiation factor TFIIIB . Its structure is composed of a central five-stranded antiparallel β-sheet that is flanked by one helix on one side and three helices on the other .
Proteinase, regulatory CLIP domain superfamily (CLIP_sf)
Type: Homologous_superfamily

The CLIP domain is a regulatory domain which controls the proteinase action of various proteins of the trypsin family, e.g. easter and pap2. The domain is restricted to the arthropoda and found in varying copy numbers (from one to five in Drosophila proteins). It is always found N-terminal to the chymotrypsin serine protease domain, which belong to MEROPS peptidase family S1A. The CLIP domain remains linked to the protease domain after cleavage of a conserved residue which retains the protein in zymogen form. It is named CLIP because it can be drawn in the shape of a paper clip. It has many disulphide bonds and highly conserved cysteine residues, and so it folds extensively .

The clip domain adopts an α/β mixed fold consisting of two helices and an antiparallel distorted β-sheet made of four strands. The two helices are antiparallel and are almost perpendicular to the β-sheet. Three disulfide bridges (C1-C5, C2-C4, C3-C6) stabilize the β-sheet, C3 being the only cysteine that is not located on a β-strand. The clip domain is located opposite the activation loop and contacts the C-terminal α-helix of the SP domain .
Mediator complex, subunit Med6 superfamily (Mediator_Med6_sf)
Type: Homologous_superfamily

This superfamily represents the core domain of the Mediator complex subunit 6 (MED6) that is required for activation of many RNA polymerase II promoters and which is conserved from yeast to humans .

The Mediator complex is a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. The Mediator complex is composed of 20 subunits in yeast and 26 subunits in humans. The subunits form at least three structurally distinct submodules. The head and the middle modules interact directly with RNA polymerase II, whereas the elongated tail module interacts with gene-specific regulatory proteins. A 4 subunit kinase module, the CDK8 module, can reversibly associate with the Mediator complex .

The head module contains: MED6, MED8, MED11, SRB4/MED17, SRB5/MED18, ROX3/MED19, SRB2/MED20 and SRB6/MED22.

The middle module contains: MED1, MED4, NUT1/MED5, MED7, CSE2/MED9, NUT2/MED10, SRB7/MED21 and SOH1/MED31. CSE2/MED9 interacts directly with MED4.

The tail module contains: MED2, PGD1/MED3, RGR1/MED14, GAL11/MED15 and SIN4/MED16.

The CDK8 module contains: MED12, MED13, CCNC and CDK8.
Transcription elongation factor 1 superfamily (T_Elf1_sf)
Type: Homologous_superfamily

Transcription elongation factor 1 (Elf1) is a transcription elongation factor implicated in the maintenance of proper chromatin structure in actively transcribed regions .
Hepatitis C virus NS5A, 1B domain superfamily (HCV_NS5A_1B_sf)
Type: Homologous_superfamily

The exact function of the Hepatitis C non-structural 5A (NS5A) protein is not known, but it is an active component of the replicase, regulates replication and modulates a range of cellular processes including innate immunity and dysregulated cell growth. NS5A is organised into three domains, labelled I, II and III. Domain I contains a zinc-binding motif and an amphipathic N-terminal helix which promotes membrane association. Mutations disrupting either the membrane anchor or zinc binding are lethal for RNA replication .

This entry represents the 1b domain of NS5A. It consists of two distinct anti-parallel β-sheets surrounded by extensive random coil structures . This domain contains a disulphide bond near its C-terminal not required for the RNA replicase functions of NS5A. The presence of the cited sulphide bond suggests that it is likely responsible of the structural arrangement of domains II and III, thus playing a regulatory role in NS5A function by serving as a conformation switch to modulate functions of NS5A in and out of the replicase .
Bacteriophage T4, IpI C-terminal domain superfamily (Phage_T4_IpI_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal region of the internal protein I (IpI) from bacteriophage T4. This protein is a nuclease inhibitor which is injected by T4 to protect its DNA from gmrS/gmrD CT of pathogenic Escherichia coli into the infected host . The structure of this protein consists of two small β-sheets flanked by N and C termini by α-helices. The protein has a gmrS/gmrD hydrophobic binding site .
HicA superfamily (HicA_sf)
Type: Homologous_superfamily

This entry represents the HicA mRNA interferase superfamily, which form the toxic component of a toxin-antitoxin (TA) module . Members contain a double-stranded RNA-binding domain and probably act as translation-independent mRNA interferases. They may form a complex with the antitoxin HicB which inhibits their mRNA interferase activity .
Bifunctional carbon monoxide dehydrogenase/acetyl-coa synthase, domain 3 superfamily (CO_DH/Ac-CoA_synth_bsu_3_sf)
Type: Homologous_superfamily

The carbon monoxide dehydrogenase alpha subunit (

) catalyses the interconversion of CO and CO2 and the synthesis of acteyl-coA from the methylated corrinoid/iron sulphur protein, CO and CoA. Nomenclature follows the description for Methanosarcina thermophila. The complex is also found in Archaeoglobus fulgidus, not considered a methanogen, but is otherwise generally associated with methanogenesis.
Stomagen, C-terminal domain superfamily (Stomagen_C_sf)
Type: Homologous_superfamily

Stomagen (epidermal patterning factor-like protein 9) is a defensin-like secretory epidermal patterning factor (EPF) peptide hormones which acts as a positive regulator of stomatal development .

The structure of stomagen is composed of a loop and a scaffold containing three disulphide bonds .
Ribonuclease toxin BrnT superfamily (BrnT_sf)
Type: Homologous_superfamily

BrnT is a ribonuclease toxin of a type II toxin-antitoxin system that exhibits a RelE-like fold. The antitoxin that neutralises this toxin is BrnA. BrnT is found in bacteria, archaea, bacteriophage, and plasmids. BrnT-BrnA forms a 2:2 tetrameric complex and autoregulates its own expression, which is induced by a number of different environmental stresses. Expression of BrnT alone results in cessation of bacterial growth which can be rescued after subsequent expression of BrnA .
E6 superfamily (E6_sf)
Type: Homologous_superfamily

The papillomavirus E6 oncoproteins are small zinc-binding proteins that share a conserved zinc-binding CXXC motif and do not have identified intrinsic enzymatic activity. E6 proteins are thought to act as adapter proteins, thereby altering the function of E6-associated cellular proteins. This model for E6 function is best supported by observations of human papillomavirus type 16 (HPV-16) E6 (16E6), which can alter the metabolism of the p53 tumor suppressor through association with a cellular E3 ubiquitin ligase called E6AP. HPV-16 E6 interacts with an 18-amino-acid sequence in E6AP, and in an as yet ill-defined fashion the E6AP-16E6 complex binds to p53, inducing the ubiquitin-dependent degradation of the trimolecular complex. 16E6 apparently functions as an adapter protein in the complex with p53, since E6AP does not interact with p53 in the absence of E6 and since the degradation of p53 requires both E6 and E6AP .

Despite the similarity in structure of the E6 oncoproteins, studies have indicated surprising biochemical diversity among E6 oncoproteins of different papillomavirus types. E6 from the cancer-associated human papillomaviruses (HPVs) complex with a cellular protein termed E6-AP and together with E6-AP bind to the p53 tumor suppressor protein thereby degrading p53 through ubiquitin-mediated proteolysis. E6 from the non-cancer-associated HPV types do not bind E6-AP or degrade p53. Bovine papilloma virus E6 (BE6) binds E6-AP but fails either to complex with p53 or to degrade associated proteins, implying that BE6 might transform cells through a mechanism different from that of the HPVs. In addition to targeting p53, E6 of both cancer-associated HPVs and BPV-1 have been shown to associate with a cellular-calcium-binding protein localized to the endoplasmic reticulum .
Methyltransferase putative zinc binding domain superfamily (Methyltransf_Zn-bd_dom_put_sf)
Type: Homologous_superfamily

This domain is found at the N terminus of bacterial methyltransferases and contains four conserved cysteines suggesting a potential role in zinc binding.
GT10-like, C-terminal domain superfamily (GT10-like_C_sf)
Type: Homologous_superfamily

Structural domains comprising this superfamily share the structure of the C-terminal domain of Glycosyltransferase family 10 (GT10). The C-terminal domain plays an important role in acceptor binding and specificity .

Glycosyltransferase family 10 (

) comprises enzymes with two known activities; galactoside 3(4)-L-fucosyltransferase (

) and galactoside 3-fucosyltransferase (

).

The galactoside 3-fucosyltransferases display similarities with the alpha-2 and alpha-6-fucosyltranferases . The biosynthesis of the carbohydrate antigen sialyl Lewis X (sLe(x)) is dependent on the activity of an galactoside 3-fucosyltransferase. This enzyme catalyses the transfer of fucose from GDP-beta-fucose to the 3-OH of N-acetylglucosamine present in lactosamine acceptors .
GT29-like superfamiliy (GT29-like_sf)
Type: Homologous_superfamily

Glycosyltransferase family 29 (

) comprises enzymes with a number of known activities; sialyltransferase (

), beta-galactosamide alpha-2,6-sialyltransferase (

), alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase (

), beta-galactoside alpha-2,3-sialyltransferase (

), N-acetyllactosaminide alpha-2,3-sialyltransferase (

), alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase (

); lactosylceramide alpha-2,3-sialyltransferase (

). These enzymes use a nucleotide monophosphosugar as the donor (CMP-NeuA) instead of a nucleotide diphosphosugar.