SII-SWORD/CoKE huggingface dataset:
Large ribosomal subunit protein eL21 (Ribosomal_eL21)
Type: Family

The eL21 family contains proteins from a number of eukaryotic and archaebacterial organisms which include mammalian eL21, Entamoeba histolytica eL21, Caenorhabditis elegans eL21 (C14B9.7), Saccharomyces cerevisiae (Baker's yeast) eL21 (URP1) and Haloarcula marismortui eL21 (HL31).

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 .
Alpha carbonic anhydrase domain (CA_dom)
Type: Domain

This entry represents a domain characteristic of alpha class carbonic anhydrases. The dominating secondary structure is a 10-stranded, twisted β-sheet, which divides the molecules into two halves . Alpha-CAs contain a single zinc atom bound to three conserved histidine residues. The catalytically active group is the zinc-bound water which ionizes to a hydroxide group. In the mechanism of catalysis, nucleophilic attack of CO2 by a zinc-bound hydroxide ion is followed by displacement of the resulting zinc-bound bicarbonate ion by water; subsequent deprotonation regenerates the nucleophilic zinc-bound hydroxide ion .

A carbonic anhydrase-like domain with striking homology to that of the alpha class carbonic anhydrases is also found in receptor-type tyrosine-protein phosphatase gamma and zeta. In this case it may have a different function, as only one of the three His residues that ligate the zinc atom and are required for catalytic activity is conserved .

Carbonic anhydrases (CA:

) are zinc metalloenzymes which catalyse the reversible hydration of carbon dioxide to bicarbonate . The alpha-CAs are found predominantly in animals but also in bacteria and green algae. There are at least 15 isoforms found in mammals, which can be subdivided into cytosolic CAs (CA-I, CA-II, CA-III, CA-VII and CA XIII), mitochondrial CAs (CA-VA and CA-VB), secreted CAs (CA-VI), membrane-associated (CA-IV, CA-IX, CA-XII and CA-XIV) and those without CA activity, the CA-related proteins (CA-RP VIII, X and XI).
Glycine radical domain (Gly_radical)
Type: Domain

Glycyl radical enzymes are involved in a great variety of functions, including nucleotide, pyruvate and toluene metabolism . A glycyl radical is formed by the removal of a hydrogen from a glycine and the resulting radical is located on the protein main chain.

Escherichia coli formate C-acetyltransferase (

) is a key enzyme of anaerobic glucose metabolism; it converts pyruvate and CoA into acetyl-CoA and pyruvate. It is posttranslationally interconverted, under anaerobic conditions, from an inactive to an active form that carries a stable radical localised to a specific glycine at the C terminus . Such a glycine radical is also present in E. coli (gene nrdD) and Bacteriophage T4 (gene nrdD or sunY) anaerobic ribonucleoside-triphosphate reductases (

). In these enzymes the glycyl radical is located at the C-terminal part of the enzyme . An autonomous glycyl radical cofactor also exists in Escherichia coli and bacteriophage T4 (gene grcA) .

This entry represents a domain covering the conserved region around the glycine radical.
G protein-coupled receptor 6 (GPR6)
Type: Family

G protein-coupled receptor 12 (GPR12) was initially isolated from a rat pituitary library, and is found in discrete regions of the brain, pituitary and testis, but is absent in other tissues . Three human homologues (GPR12, GPR6 and GPR3) have also been isolated . The 3 genes have been localised to human chromosomal regions 13q12, 6q21
and 1p34.3-p36.1 respectively.

This entry represents G protein-coupled receptor 6, which is an orphaned receptor, no endogenous ligand having yet been identified.
Beta-thymosin (Beta-thymosin)
Type: Family

This entry represents beta-thymosin family. Its members include thymosin beta-4, -10, -15 from humans and their homologues (such as thymosin beta 11/12) from fish.

Thymosin beta-4 (Tbeta) is a small protein that sequesters actin monomers to help maintain the high concentrations of unpolymerised actin in higher eukaryotic cells. Its structure has been resolved . It is a multiple function protein that plays important roles in cellular processes such as wound healing, embryonic organ development and the pathogeneses of disease . It plays a role in anti-apoptotic response to an external stress , paclitaxel-resistance via ROS production and HIF-1alpha stabilisation via Erk activation . It also regulates cancer cell migration through various signalling pathways, and hence plays a role in malignant progression and invasion in colon adenocarcinoma .
Barwin domain (Barwin_dom)
Type: Domain

Barwin is a basic protein isolated from aqueous extracts of barley seeds. It is 125 amino acids in length, and contains six cysteine residues that combine to form three disulphide bridges . Comparative analysis shows the sequence to be highly similar to a 122 amino acid stretch in the C-terminal of the products of two wound-induced genes (win1 and win2) from potato, the product of the hevein gene of rubber trees, and pathogenesis-related protein 4 from tobacco. The high levels of similarity to these proteins, and their ability to bind saccharides, suggest that the barwin domain may be involved in a common defence mechanism in plants.
DNA topoisomerase II, eukaryotic-type (TopoII_euk)
Type: Family

This entry represents DNA topoisomerase II enzymes from eukaryotes and viruses. Topoisomerase II primarily functions in introducing negative supercoils into DNA, and is of particular importance during the segregation of chromosomes during mitosis . In eukaryotes and viruses, this enzyme occurs as a single polypeptide, with the N-terminal portion (homologous to subunit B of bacterial topoisomerase II, or gyraseB) responsible for ATPase activity and the C-terminal portion (homologous to subunit A of bacterial topoisomerase II, or gyraseA) responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges. In mammals, there are at least two isozymes of this enzyme, topoisomerases II-alpha and II-beta, which are similar in structure and catalytic properties . The alpha isoform is involved in chromosome condensation and segregation.

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .

Type II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils .
NADH:flavin oxidoreductase/NADH oxidase, N-terminal (OxRdtase_FMN_N)
Type: Domain

The TIM-barrel fold is a closed barrel structure composed of an eight-fold repeat of β-α units, where the eight parallel β strands on the inside are covered by the eight α helices on the outside . It is a widely distributed fold which has been found in many enzyme families that catalyse completely unrelated reactions . The active site is always found at the C-terminal end of this domain.

Proteins in this entry are a variety of NADH:flavin oxidoreductase/NADH oxidase enzymes, found mostly in bacteria or fungi, that contain a TIM-barrel fold. They commonly use FMN/FAD as cofactor and include:

dimethylamine dehydrogenase

trimethylamine dehydrogenase

12-oxophytodienoate reductase

NADPH dehydrogenase

NADH oxidase
Transferrin-like domain (Transferrin-like_dom)
Type: Domain

Transferrins are eukaryotic iron-binding glycoproteins that control the level of free iron in biological fluids . Evidence suggests that members of the TF family arose from the duplication and fusion of two homologous domains, with each duplicated domain binding one iron atom. Members of the family include blood serotransferrin (siderophilin); milk lactotransferrin (lactoferrin); egg white ovotransferrin (conalbumin); and membrane-associated melanotransferrin. Family members that do not bind iron have also been discovered, including inhibitor of carbonic anhydrase (ICA), which strongly binds to and inhibits certain isoforms of carbonic anhydrase .

This entry represents the transferrin-like domain, which can be further divided into two subdomains that form a cleft inside of which the iron atom is bound in iron-transporting transferrin . The iron-coordinating residues consist of an aspartic acid, two tyrosines and a histidine, as well as an arginine that coordinates a requisite anion. In addition to iron and anion liganding residues, the transferrin-like domain contains conserved cysteine residues involved in disulphide bond formation.
Non-structural protein NS1, flavivirus (Flavi_NS1)
Type: Domain

The Flavivirus genome polypepetide contains the capsid protein C (core protein), the matrix protein (envelope protein M), the major envelope protein E, a number of small non structural proteins (NS1, NS2A, NS2B, NS4A and NS4B), helicase and RNA-directed polymerase (NS5) .
DIX domain (DIX)
Type: Domain

Proteins of the dishevelled family (Dsh and Dvl) play a key role in the transduction of the Wg/Wnt signal from the cell surface to the nucleus: in response to Wnt signal, they block the degradation of beta- catenin by interacting with the scaffolding protein axin. The N terminus of proteins of the dishevelled family and the C terminus of proteins of the axin family share a region of homology of about 85 amino acids, which has been called DIX for DIshevelled and aXin . The DIX domain is found associated with PDZ and DEP domains in proteins of the dishevelled family and with an RGS domain in proteins of the axin family. DIX has been shown to be a protein-protein interaction domain that is important for homo- and hetero-oligomerization of proteins of the dishevelled and axin families . The DIX domain has also be shown to be a signalling module that can target proteins to actin stress fibres and cytoplasmic vesicles to control Wnt signalling .

The Dvl2 DIX domain has been shown to form a predominantly helical structure .

A third type of DIX domain-possessing protein, known as Coiled-coil-DIX1 (Ccd1) or Dixin, forms homomeric and heteromeric complexes with Dvl and Axin and is positive regulator of Wnt signaling .
Peptidase M20C, Xaa-His dipeptidase (Peptidase_M20C)
Type: Family

This majority of this group of proteins are aminoacyl-histidine dipeptidases (Xaa-His dipeptidases, cytosol non-specific dipeptidases, peptidase D), which are zinc-containing metallopeptidases that belong to MEROPS peptidase family M20 (clan MH), subfamily M20C . Proteins of this clan have two catalytic zinc ions at the active site, bound by His/Asp, Asp, Glu, Asp/Glu and His . The catalysed reaction involves the release of an N-terminal amino acid, usually neutral or hydrophobic, from a polypeptide .
Helicase XPB/Ssl2 (XPB/Ssl2)
Type: Family

XPB, also known as Ssl2, Ercc3, RepB, Rad25 or haywire, is a core subunit of the eukaryotic basal transcription factor complex TFIIH, which plays a dual role in transcription and DNA repair . It is involved in nucleotide excision repair of DNA and in RNA transcription by RNA polymerase II . TFIIH is a multiprotein complex composed of a 7-subunit core, including XPB, p62, p52, p44, p34 and TTDA, associated with a 3-subunit CDK-activating kinase module consisting of MAT1, cyclin H and Cdk7 . XPB functions by opening DNA either around the RNA transcription start site or at sites of DNA damage . It is also required for spliced leader RNA gene transcription by RNA polymerase II, where TFIIH plays an essential role in transcription initiation . Once the pre-initiation complex has been established, TFIIH is necessary for promoter opening and promoter escape, processes that depend on the ATPase activity of XPB .
UvrC, RNAse H endonuclease domain (UvrC_RNase_H_dom)
Type: Domain

Nucleotide excision repair (NER) is a conserved DNA repair pathway that enables the repair of chemically and structurally distinct DNA lesions. In prokaryotes, the UvrA, UvrB and UvrC proteins mediate NER in a multistep, ATP-dependent reaction. UvrC catalyses the first incision on the fourth or fifth phosphodiester bond 3' and on the eighth phosphodiester bond 5' from the damage that is to be excised. UvrC proteins contain conserved regions: the GIY-YIG domain, the cys-rich region, the UvrBC domain which interacts with uvrB, the RNAse H endonuclease domain and the Helix hairpin Helix (HhH)2 domain .

This entry represents the RNAse H endonuclease domain, located at the C-terminal, between the UvrBC and the (HhH)2 domains, nearby the N-terminal of the HhH. Despite the lack of sequence homology, the endonuclease domain has an RNase H-like fold, which is characteristic of enzymes with nuclease or polynucleotide transferase activities. RNase H-related enzymes typically contain a highly conserved carboxylate triad, usually DDE, in their catalytic centre. However, instead of a third carboxylate, UvrC of Thermotoga maritima was found to contain a highly conserved histidine (H488) on helix-4 in close proximity to two aspartates .
Sm domain, eukaryotic/archaea-type (Sm_dom_euk/arc)
Type: Domain

This domain is found in Lsm (like-Sm) proteins, which have a core structure consisting of an open β-barrel with an SH3-like topology.

Lsm (like-Sm) proteins have diverse functions, and are thought to be important modulators of RNA biogenesis and function . The Sm proteins form part of specific small nuclear ribonucleoproteins (snRNPs) that are involved in the processing of pre-mRNAs to mature mRNAs, and are a major component of the eukaryotic spliceosome. Most snRNPs consist of seven Sm proteins (B/B', D1, D2, D3, E, F and G) arranged in a ring on a uridine-rich sequence (Sm site), plus a small nuclear RNA (snRNA) (either U1, U2, U5 or U4/6) . All Sm proteins contain a common sequence motif in two segments, Sm1 and Sm2, separated by a short variable linker . Other snRNPs, such as U7 snRNP, can contain different Lsm proteins.

Lsm proteins are also found in archaebacteria, which do not have any splicing apparatus, suggesting a more general role for Lsm proteins. Archaeal Lsm proteins have been shown to bind to small RNAs and are probably involved in many cellular processes . Archaeal Lsm proteins are likely to represent the ancestral Lsm domain .
Arf GTPase activating protein (ArfGAP_dom)
Type: Domain

Proteins containing this domain include ARF1-directed GTPase-activating protein, the cycle control GTPase activating protein (GAP) GCS1 which is important for the regulation of the ADP ribosylation factor ARF, a member of the Ras superfamily of GTP-binding proteins . The GTP-bound form of ARF is essential for the maintenance of normal Golgi morphology, it participates in recruitment of coat proteins which are required for budding and fission of membranes. Before the fusion with an acceptor compartment the membrane must be uncoated. This step required the hydrolysis of GTP associated to ARF. These proteins contain a characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-x2-Cys) which displays some similarity to the C4-type GATA zinc finger. The ARFGAP domain display no obvious similarity to other GAP proteins.

The 3D structure of the ARFGAP domain of the PYK2-associated protein beta has been solved . It consists of a three-stranded β-sheet surrounded by 5 α helices. The domain is organised around a central zinc atom which is coordinated by 4 cysteines. The ARFGAP domain is clearly unrelated to the other GAP proteins structures which are exclusively helical. Classical GAP proteins accelerate GTPase activity by supplying an arginine finger to the active site. The crystal structure of ARFGAP bound to ARF revealed that the ARFGAP domain does not supply an arginine to the active site which suggests a more indirect role of the ARFGAP domain in the GTPase hydrolysis .
T4-type lysozyme (T4-type_lysozyme)
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 24 (

) comprises enzymes with only one known activity; lysozyme (

).

T4 lysozyme helps to release mature phage particles from the cell wall by breaking down the peptidoglycan. The enzyme hydrolyses the 1,4-beta linkages between N-acetyl-D-glucosamine and N-acetylmuramic acid in peptidoglycan heteropolymers of prokaryotic cell walls.

The T4 lysozyme structure contains 2 domains, the interface between which forms the active-site cleft. The N terminus of the 2 domains undergoes a 'hinge-bending' motion about an axis passing through the molecular waist . This mobility is thought to be important in allowing access of substrates to the enzyme active site.
Hyperglycemic hormone (Hyperglycemic)
Type: Family

Hyperglycemic hormone, which controls blood sugar levels, is an abundant peptide in the sinus glands of isopods and decapods . The peptide is a potent secretagogue, releasing digestive enzymes from the hepatopancreas. It may act as a stress hormone. The peptide contains around 70 amino acid residues, and includes six cysteine residues involved in disulphide bond formation . The sequences show a high degree of similarity to the American lobster molt-inhibiting hormone , which also shows hyperglycemic hormone activity.

Sequence analysis reveals at least 2 discrete sequence families, characterised by distinctive N- and C-terminal signatures: broadly, the families represent separate groups of the crustacean hyperglycemic-like hormones and the molt-inhibiting-like hormones. The positions of five of the six cysteine residues are conserved between these families, the first Cys being displaced by one residue position.
Adrenocorticotrophin (ACTH) receptor (ACTH_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 .

Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones and beta-endorphin are peptide products of pituitary pro-opiomelanocortin. ACTH regulates synthesis and release of glucocorticoids and aldosterone in the adrenal cortex; it also has a trophic action on these cells. ACTH and beta-endorphin are synthesised and released in response to corticotrophin-releasing factor at times of stress (heat, cold, infections, etc.) -their release leads to increased metabolism and analgesia. The ACTH receptor is found in high levels in the adrenal cortex -binding sites are present in lower levels in the CNS.
Adenylyl cyclase class-4/guanylyl cyclase (ANPR/GUC)
Type: Family

This entry includes the natriuretic peptide receptors (ANP-A, ANP-B and ANP-C) from animals and guanylate cyclases 2G (GUC2G) from rodents. GUC2G is closely related to the natriuretic peptide receptors, but all ligands known to activate other receptors failed to stimulate its enzymic activity .

Natriuretic peptides are hormones involved in the regulation of fluid and electrolyte homeostasis. These hormones stimulate the intracellular production of cyclic GMP as a second messenger. They belong to a family that includes extracellular ligand binding domains of a wide range of receptors. Three peptide receptors are known, two of which express quanylate cyclase activity (GC-A or ANP-A, and GC-B or ANP-B), while the third (ANP-C) is probably responsible for the clearance of atrial natriuretic peptide (ANP) from the circulation and does not play a role in signal transduction .

GC-A and GC-B are plasma membrane-bound proteins that share the following topology: an N-terminal extracellular domain which acts as the ligand binding region, then a transmembrane domain followed by a large cytoplasmic C-terminal region that can be subdivided into two domains: a protein kinase-like domain

that appears important for proper signalling and a guanylate cyclase catalytic domain

. The topology of ANP-C is different: like GC-A and -B it possesses an extracellular ligand-binding region and a transmembrane domain, but its cytoplasmic domain is very short.