SII-SWORD/CoKE huggingface dataset:
Zinc finger, SIAH-type (Znf_SIAH)
Type: Domain

SINA/Siah family proteins represent mammalian homologs of the Drosophila SINA (seven in absentia) protein. SINA is required for R7 photoreceptor cell differentiation within the sevenless pathway . Members of this family are E3 ubiquitin ligases that regulate ubiquitination and protein degradation. Siahs are known to recognise several target proteins including Deleted in Colorectal Cancer (DCC), synaptophysin and Numb and promote their degradation .

SINA/Siah sequences are highly conserved from plants to mammals. Whereas the N terminus and RING domain of Siah bind E2 proteins, the C terminus can be considered as a substrate- and cofactor-interaction domain (substrate-binding domain, SBD) that interacts with a number of proteins, some of which are degraded . The SBD domain displays some sequence similarities with the C-terminal region of TRAF proteins. It contains a cysteine-rich region, the SIAH-type zinc finger, with eight totally conserved Cys and His residues that coordinate two zinc atoms . The crystal structure of SIAH-type zinc finger has been solved . It folds in two subdomains, each one binding one zinc atom and consisting of two β-strands and an α-helix.

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Phosphotransferase system, EIIB component, type 3 (PTS_EIIB_3)
Type: Domain

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyses the phosphorylation of incoming sugar substrates and coupled with translocation across the cell membrane, makes the PTS a link between the uptake and metabolism of sugars.

The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred via a signal transduction pathway, to enzyme I (EI) which in turn transfers it to a phosphoryl carrier, the histidine protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease, a membrane-bound complex known as enzyme 2 (EII), which transports the sugar to the cell. EII consists of at least three structurally distinct domains IIA, IIB and IIC . These can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).

According to structural and sequence analyses, the PTS EIIB domain (

) can be divided in five groups :

The PTS EIIB type 1 domain, which is found in the Glucose class of PTS, has an average length of about 80 amino acids. It forms a split α/β sandwich composed of an antiparallel sheet (beta 1 to beta 4) and three α helices superimposed onto one side of the sheet. The phosphorylation site (Cys) is located at the end of the first β strand on a protrusion formed by the edge of β1 and the reverse turn between β1 and β2 .

The PTS EIIB type 2 domain, which is found in the Mannitol and Fructose class of PTS, has an average length of about 100 amino acids. It consists of a four stranded parallel β sheet flanked by two α helices (α1 and 3) on one face and helix α2 on the opposite face, with a characteristic Rossmann fold comprising two right-handed β-α-β motifs. The phosphorylation site (Cys) is located at the N terminus of the domain, in the first β strand.

The PTS EIIB type 3 domain, which is found in the Lactose class of PTS, has an average length of about 100 amino acids. It is composed of a central four-stranded parallel open twisted β sheet, which is flanked by three α helices on the concave side and two on the convex side of the β sheet. The phosphorylation site (Cys) is located in the C-terminal end of the first β strand .

The PTS EIIB type 4 domain, which is found in the Mannose class of PTS, has an average length of about 160 amino acids. It has a central core of seven parallel β strands surrounded by a total of six α-helices. Three helices cover the front face, one the back face with the remaining two capping the central β sheet at the top and bottom. The phosphorylation site (His) is located at the surface exposed loop between strand 1 and helix 1 .

The PTS EIIB type 5 domain, which is found in the Sorbitol class of PTS, has an average length of about 190 amino acids. The phosphorylation site (Cys) is located in the N terminus of the domain.

The EIIB type 3 domain is often found downstream of the EIIC type 3 domain.
Phosphotransferase system, EIIC component, type 1 (PTS_EIIC_1)
Type: Domain

According to sequence analyses , the PTS EIIC domain can be divided in five groups:

The PTS EIIC type 1 domain is found in the Glucose class of PTS and has an average length of about 80 amino acids.

The PTS EIIC type 2 domain is found in the Mannitol class of PTS and has an average length of about 90 amino acids.

The PTS EIIC type 3 domain is found in the Lactose class of PTS and has an average length of about 100 amino acids.

The PTS EIIC type 4 domain is found in the Mannose class of PTS and has an average length of about 160 amino acids.

The PTS EIIC type 5 domain is found in the Sorbitol class of PTS and has an average length of about 190 amino acids.

This entry represents the type 1 domain.

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyses the phosphorylation of incoming sugar substrates and coupled with translocation across the cell membrane, makes the PTS a link between the uptake and metabolism of sugars.

The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred via a signal transduction pathway, to enzyme I (EI) which in turn transfers it to a phosphoryl carrier, the histidine protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease, a membrane-bound complex known as enzyme 2 (EII), which transports the sugar to the cell. EII consists of at least three structurally distinct domains IIA, IIB and IIC . These can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).
Phosphotransferase system, EIIC component, type 2 (PTS_EIIC_2)
Type: Domain

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyses the phosphorylation of incoming sugar substrates and coupled with translocation across the cell membrane, makes the PTS a link between the uptake and metabolism of sugars.

The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred via a signal transduction pathway, to enzyme I (EI) which in turn transfers it to a phosphoryl carrier, the histidine protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease, a membrane-bound complex known as enzyme 2 (EII), which transports the sugar to the cell. EII consists of at least three structurally distinct domains IIA, IIB and IIC . These can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).

According to sequence analyses , the PTS EIIC domain can be divided in five groups:

The PTS EIIC type 1 domain is found in the Glucose class of PTS and has an average length of about 80 amino acids.

The PTS EIIC type 2 domain is found in the Mannitol class of PTS and has an average length of about 90 amino acids.

The PTS EIIC type 3 domain is found in the Lactose class of PTS and has an average length of about 100 amino acids.

The PTS EIIC type 4 domain is found in the Mannose class of PTS and has an average length of about 160 amino acids.

The PTS EIIC type 5 domain is found in the Sorbitol class of PTS and has an average length of about 190 amino acids.

This entry represents the type 2 domain.
Laminin IV type B (Laminin_IV_B)
Type: Domain

Laminin is a large molecular weight glycoprotein present only in basement membranes in almost every animal tissue. Each laminin is a heterotrimer assembled from alpha, beta and gamma chain subunits, secreted and incorporated into cell-associated extracellular matrices. The laminins can self-assemble, bind to other matrix macromolecules, and have unique and shared cell interactions mediated by integrins, dystroglycan, and other receptors. Through these interactions, laminins critically contribute to cell differentiation, shape and movement, maintenance of tissue phenotypes, and promotion of tissue survival .
Peptidase C16, coronavirus (Peptidase_C16_CoV)
Type: Domain

This entry contains coronavirus (CoV) cysteine endopeptidases that belong to MEROPS peptidase family C16 (subfamilies C16A and C16B, clan CA). These peptidases are involved in viral polyprotein processing, releasing NSP1, NSP2 and NSP3 proteins and they also function as deubiquitinating and deISG15ylating (interferon-induced gene 15) enzymes, disrupting host viral immune response to facilitate viral proliferation and replication. Therefore, this is an important target to develop antiviral treatments .

All coronaviruses encode between one and two accessory cysteine proteinases that recognise and process one or three sites in the amino-terminal half of the replicase polyprotein during assembly of the viral replication complex. MHV, HCoV and TGEV encode two accessory proteinases, called coronavirus papain-like proteinase 1 and 2 (PL1-PRO and PL2-PRO) . IBV and SARS encodes only one called PL-PRO (PL2-PRO, conserved in all CoVs) . The structures of both PL-PROs are similar and they also have restricted specificities. The PL1-PRO of TGEV cleaves the polyprotein between Nsp2-Nsp3 recognising the Lys-Met-Gly-Gly motif, and recognises Leu-Arg-Gly-Gly in ubiquitin (ub) which shows that it is able to accommodate residues as different as Lys and Leu. In contrast, PL-PRO from SARS-CoV recognises Leu-Xaa-Gly-Gly (Xaa could be any amino acid) and cleaves peptide bonds between Nsp1-Nsp2, Nsp2-Nsp3 and between Nsp3-Nsp4 . In Ub and ISG15 proteins, it recognises Leu-Arg-Gly-Gly motifs. SARS-CoV and SARS-CoV-2 are closely related but exhibit different host substrate preferences: SARS-CoV-2 PL-PRO preferentially cleaves the ubiquitin-like ISG15, whereas SARS-CoV PL-PRO predominantly targets ubiquitin chains .

The peptidase family C16 domain is about 260 amino acids in length and the solved structures determined that it consists of thumb, palm, and fingers subdomains. The thumb is comprised of six α-helices and a small β-hairpin; the fingers subdomain is made of six β-strands and two α-helices and includes a zinc binding site, in which the zinc ion is coordinated by four cysteine residues. Zinc binding is essential for structural integrity and protease activity, with a conformation that varies most between different PL-PRO structures. The palm subdomain is comprised of six β-strands and includes the catalytic residues Cys-His-Asp, located at the interface between the thumb and palm subdomains .
MAD homology, MH1 (MAD_homology_MH1)
Type: Domain

Smad proteins are signal transducers and transcriptional comodulators of the TGF-beta superfamily of ligands, which play a central role in regulating a broad range of cellular responses, including cell growth, differentiation, and specification of developmental fate, in diverse organisms from Caenorhabditis elegans to humans. Ligand binding to specific transmembrane receptor kinases induces receptor oligomerisation and phosphorylation of the receptor specific Smad protein (R-Smad) in the cytoplasm. The R-Smad proteins regulate distinct signalling pathways. Smad1, 5 and 8 mediate the signals of bone morphogenetic proteins (BMPs), while Smad2 and 3 mediate the signals of activins and TGF-betas. Upon ligand stimulation, R-Smad proteins are phosphorylated at the conserved C-terminal tail sequence, SS*xS* (where S* denotes a site of phosphorylation). The phosphorylated states of R-Smad proteins form heteromeric complexes with Smad4 and are translocated into the nucleus. In the nucleus, the heteromeric complexes function as gene-specific transcription activators by binding to promoters and interacting with transcriptional coactivators. Smad6 and Smad7 are inhibitory Smad proteins that inhibit TGF-beta signalling by interfering with either receptor-mediated phosphorylation or hetero-oligomerisation between Smad4 and R-Smad proteins. Smad proteins comprise two conserved MAD homology domains, one in the N terminus (MH1) and one in the C terminus (MH2), separated by a more variable, proline-rich linker region. The MH1 domain has a role in DNA binding and negatively regulates the functions of MH2 domain, whereas the MH2 domain is responsible for transactivation and mediates phosphorylation-triggered heteromeric assembly between Smad4 and R-Smad .
ATP-dependent helicase Rad3/Chl1-like (Rad3/Chl1-like)
Type: Family

This entry includes a group of ATP-dependent helicases, including Rad3/XPD (ERCC2), Chl1/DDX11, DDX12, RTEL1 and BRIP1. Rad3/XPD is a subunit of RNA polII initiation factor TFIIH and of Nucleotide Excision Repair Factor 3 (NEF3) . DDX11/Chl1 is required for sister-chromatid cohesion .
Myo-inositol-1-phosphate synthase, GAPDH-like (Myo-inos-1-P_Synthase_GAPDH)
Type: Domain

This is a region of myo-inositol-1-phosphate synthases that is related to the glyceraldehyde-3-phosphate dehydrogenase-like, C-terminal domain.
Xylose isomerase-like, TIM barrel domain (Xyl_isomerase-like_TIM-brl)
Type: Domain

This entry represents a structural motif with a β/α TIM barrel found in several proteins families:

Endonuclease IV (

), an AP (apurinic/apyrimidinic) endonuclease that primes DNA repair synthesis by cleaving the DNA backbone 5' of AP sites .

L-rhamnose isomerase (

), a tetramer of four TIM barrels that catalyses the isomerisation between aldoses and ketoses, such as between L-rhamnose and L-rhamnulose .

Xylose isomerase (

), which catalyses the first reaction in the catabolism of D-xylose by converting D-xylose to D-xylulose .

Mannonate dehydratase UxuA, which along with mannonate oxidoreductase converts D-fructuronate to 2-keto-3-deoxy-D-gluconate .

These proteins share similar, but not identical, metal-binding sites. In addition, xylose isomerase and L-rhamnose isomerase each have additional α-helical domains involved in tetramer formation.
Ketol-acid reductoisomerase (KARI)
Type: Family

Ketol-acid reductoisomerase (KARI) or acetohydroxy acid isomeroreductase catalyses the conversion of acetohydroxy acids into dihydroxy valerates. This reaction is the second in the synthetic pathway of the essential branched side chain amino acids valine and isoleucine . The enzyme forms a tetramer of similar but non-identical chains, and requires magnesium as a cofactor. Most ketol-acid reductoisomerases prefer the NADPH cofactor to NADH, but NADH-utilizing enzymes has also been identified .
Gamma-glutamyl cyclotransferase-like (GGCT-like)
Type: Domain

Gamma-glutamyl cyclotransferase (GGCT) catalyzes the formation of pyroglutamic acid (5-oxoproline) from dipeptides containing gamma-glutamyl, and is a dimeric protein. In Homo sapiens, the protein is encoded by the gene C7orf24 . The enzyme participates in the gamma-glutamyl cycle, which plays a pre-eminent role in glutathione homoeostasis . The synthesis and metabolism of glutathione (L-gamma-glutamyl-L-cysteinylglycine) ties the gamma-glutamyl cycle to numerous cellular processes; glutathione acts as a ubiquitous reducing agent in reductive mechanisms involved in protein and DNA synthesis, transport processes, enzyme activity, and metabolism.

AIG2 (avrRpt2-induced gene) is an Arabidopsis protein that exhibits RPS2- and avrRpt2-dependent induction early after infection with Pseudomonas syringae pv maculicola strain ES4326 carrying avrRpt2 . avrRpt2 is an avirulence gene that can convert virulent strains of P. syringae to avirulence on Arabidopsis thaliana, soybean, and bean. This GGCT-like domain is also found in bacterial tellurite-resistance proteins (TrgB) , butirosin biosynthesis protein BtrG , and in proteins described as ChaC, involved in a novel pathway for glutathione degradation .
Large ribosomal subunit protein uL23-like (Ribosomal_uL23-like)
Type: Family

This entry represents the large ribosomal subunit protein uL23, previously known as L25 in yeast and L23 in bacteria, archaea and some eukaryotes .

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 .
YchF, C-terminal domain (YchF_C)
Type: Domain

This domain is found at the C terminus of YchF. The crystal structure of YchF

from Haemophilus influenzae has been determined . This protein consists of three domains: an N-terminal domain which has a mononucleotide binding fold typical for the P-loop NTPases, a central domain which forms an α-helical coiled coil, and this C-terminal domain which is composed of a six-stranded half-barrel curved around an α-helix. The central domain and this domain are topologically similar to RNA-binding proteins, while the N-terminal region contains the features typical of GTP-dependent molecular switches. The purified protein was capable of binding both double-stranded nucleic acid and GTP. It was suggested, therefore, that this protein might be part of a nucleoprotein complex and could function as a GTP-dependent translation factor.
DNA topoisomerase I, DNA binding, N-terminal domain 2 (DNA_topo_DNA_db_N_dom2)
Type: Homologous_superfamily

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 I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .

This entry represents a structural motif, consisting of a complex α/β topology that forms the N-terminal DNA-binding domain of certain eukaryotic topoisomerase I (type IB) enzymes. To cleave the DNA backbone, these enzymes must make a transient phosphotyrosine bond. The N-terminal domain of human topoisomerase I is thought to coordinate the restriction of free strand rotation during the topoisomerisation step of catalysis. A conserved tryptophan residue may be important for the DNA-interaction ability of the N-terminal domain . Human topoisomerase I has been shown to be inhibited by camptothecin (CPT), a plant alkaloid with antitumour activity. A binding mode for the anticancer drug camptothecin has been proposed on the basis of chemical and biochemical information combined with the three-dimensional structures of topoisomerase I-DNA complexes .