SII-SWORD/CoKE huggingface dataset:
T4 recombination endonuclease VII, dimerisation domain superfamily (T4_recomb_endonuclease_dim_sf)
Type: Homologous_superfamily

This entry represents a dimerisation domain predominantly found in Bacteriophage T4 recombination endonuclease VII. It adopts a helical secondary structure, with three α helices oriented parallel to each other. As well as mediating dimerisation of the protein, this domain is also involved in binding to the DNA major groove .
Smp-1-like superfamily (Smp-1-like_sf)
Type: Homologous_superfamily

This entry represents a conserved region found in various eukaryotic hypothetical proteins, as well as in homologues of the cysteine protease calpain. Its function has not, as yet, been defined.
Hypothetical protein Ta0289, C-terminal (Ta0289_C)
Type: Homologous_superfamily

This domain is predominantly found in various hypothetical archaeal proteins. Its exact function has not been defined yet. It possesses a zinc ribbon fold .
Bifunctional inhibitor/plant lipid transfer protein/seed storage helical domain superfamily (Bifun_inhib/LTP/seed_sf)
Type: Homologous_superfamily

This entry represents a superfamily of structural domains consisting of 4-helices with a folded leaf topology, and forming a right-handed superhelix. This domain occurs in several proteins, including:

Plant lipid-transfer proteins, such as the non-specific lipid-transfer proteins ns-LTP1 and ns-LTP2 .

Proteinase/alpha-amylase inhibitors, such as trypsin/alpha-amylase inhibitor RBI from Eleusine coracana (Indian finger millet) and Hageman factor/amylase inhibitor from Zea mays (Maize) .

Seed storage proteins, such as napin from Brassica napus (Rape) and 2S albumin from Ricinus communis (Castor bean) .
PepX, N-terminal domain superfamily (PepX_N_dom_sf)
Type: Homologous_superfamily

This N-terminal domain adopts a secondary structure consisting of a helical bundle of eight α helices and three β strands, with the last α helix connecting to the first strand of the catalytic domain. The first strand of the N terminus also forms a small parallel β sheet with strand five of the catalytic domain. This domain mediates dimerisation of the protein, with two proline residues present in the domain being critical for interaction .
Manganese/iron superoxide dismutase, C-terminal domain superfamily (SOD_C_sf)
Type: Homologous_superfamily

Superoxide dismutases (SODs) (

) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one . This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.

The structure of Fe/MnSODs can be divided into two domains, an N-terminal domain with an α-fold and α C-terminal domain with an α/β fold, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist . The structure of the C-terminal domain is of the α/β type, and consists of a three-stranded antiparallel β-sheet in the order 213, along with four helices in the arrangement α/β2/α/β/α2 .

This superfamily describes the C-terminal domain of Manganese/iron superoxide dismutase.
BRCA2 helical domain superfamily (BRCA2_hlx_sf)
Type: Homologous_superfamily

This entry represents a domain found in BRCA2 proteins. This domain adopts a helical structure, consisting of a four-helix cluster core (α1, α8, α9, α10) and two successive β-hairpins (β1 to β4). An approximately 50-amino acid segment that contains four short helices (α2 to α4), meanders around the surface of the core structure. In BRCA2, the α9 and α10 helices pack with BRCA-2_OB1 (

) through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. This domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome .
Pili assembly chaperone, C-terminal domain superfamily (Pili_assmbl_chap_C_dom_sf)
Type: Homologous_superfamily

Most Gram-negative bacteria possess a supramolecular structure - the pili - on their surface, which mediates attachment to specific receptors. Many interactive subunits are required to assemble pili, but their assembly only takes place after translocation across the cytoplasmic membrane. Periplasmic chaperones assist pili assembly by binding to the subunits, thereby preventing premature aggregation . Pili chaperones are structurally, and possibly evolutionarily, related to the immunoglobulin superfamily : they contain two globular domains, with a topology identical to an immunoglobulin fold.

This entry represents the C-terminal domain superfamily of pili assembly chaperone PapD, and has a β-sandwich fold consisting of eight strands in two sheets with a Greek key topology.
Cullin homology domain superfamily (Cullin_homology_sf)
Type: Homologous_superfamily

Cullins are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases (E3). Cullins are found throughout eukaryotes. Humans express several cullins (Cul1, 2, 3, 4A, 4B, 5, 7 and 9), each forming part of a multi-subunit ubiquitin complex . Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) , play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins .

This entry represents the cullin-homology domain superfamily. This domain is composed of three subdomains: a 4-helical bundle domain, an α+β domain, and a winged helix-like domain.
FAD-binding, type PCMH-like superfamily (FAD-bd_PCMH-like_sf)
Type: Homologous_superfamily

This entry represents a FAD-binding domain superfamily. This domain consists of two α+β subdomains.

Flavoenzymes have the ability to catalyse a wide range of biochemical reactions. They are involved in the dehydrogenation of a variety of metabolites, in electron transfer from and to redox centres, in light emission, in the activation of oxygen for oxidation and hydroxylation reactions . About 1% of all eukaryotic and prokaryotic proteins are predicted to encode a flavin adenine dinucleotide (FAD)-binding domain .

According to structural similarities and conserved sequence motifs, FAD-binding domains have been grouped in three main families: (i) theferredoxin reductase (FR)-type FAD-binding domain (see

), (ii) the FAD-binding domains that adopt a Rossmann fold and (iii) the p-cresol methylhydroxylase (PCMH)-type FAD-binding domain .

The FAD cofactor consists of adenosine monophosphate (AMP) linked to flavin mononucleotide (FMN) by a pyrophosphate bond. The AMP moiety is composed of the adenine ring bonded to a ribose that is linked to a phosphate group. The FMN moiety is composed of the isoalloxazine-flavin ring linked to a ribitol, which is connected to a phosphate group. The flavin functions mainly in a redox capacity, being able to take up two electrons from one substrate and release them two at a time to a substrate or coenzyme, or one at a time to an electron acceptor. The catalytic function of the FAD is concentrated in the isoalloxazine ring, whereas the ribityl phosphate and the AMP moiety mainly stabilise cofactor binding to protein residues .

The PCMH-type FAD-binding domain consists of two α-β subdomains: one is composed of three parallel β-strands (B1-B3) surrounded by α-helices, and is packed against the second subdomain containing five antiparallel β-strands (B4-B8) surrounded by α-helices . The two subdomains accommodate the FAD cofactor between them . In the PCMH proteins the coenzyme FAD is also covalently attached to a tyrosine located outside the FAD-binding domain in the C-terminal catalytic domain .

This domain is found in:

FAD-linked oxidases (N-terminal domain), such as vanillyl-alcohol oxidase (

) , flavoprotein subunit of p-cresol methylhydroxylase (

) , D-lactate dehydrogenases (

,

-cytochrome) , cholesterol oxidases (

) , and cytokinin dehydrogenase 1 (

) .

Uridine diphospho-N-acetylenolpyruvylglucosamine reductase (MurB) (N-terminal domain) .

CO dehydrogenase flavoprotein (N-terminal domain; ) family, which includes xanthine oxidase (domain 3) (

) , subunit A of xanthine dehydrogenase (domain 3) (

) , medium subunit of quinoline 2-oxidoreductase (QorM) (

) , and the beta-subunit of 4-hydroxybenzoyl-CoA reductase (HrcB) (N-terminal domain) (

) .
RDM1 superfamily (RDM1_sf)
Type: Homologous_superfamily

This superfamily includes protein RDM1 from Arabidopsis, which is a a small protein that binds single-stranded methyl DNA, and associates and co-localises with RNA polymerase II, AGO4 and DRM2 in the nucleus. RDM1 is a component of the RNA-directed DNA methylation effector complex and may have a role in linking siRNA production with pre-existing or de novo cytosine methylation .
Glycosyl transferase family 3, N-terminal domain superfamily (Glycosyl_Trfase_fam3_N_dom_sf)
Type: Homologous_superfamily

The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([ec:2.4.1.-]) and related proteins into distinct sequence based families has been described . This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.

This N-terminal domain is found in various family 3 glycosyl transferases, including anthranilate phosphoribosyltransferase (TrpD,

) and thymidine phosphorylase (

). All these proteins can transfer a phosphorylated ribose substrate. Thymidine phosphorylase catalyses the reversible phosphorolysis of thymidine, deoxyuridine and their analogues to their respective bases and 2-deoxyribose 1-phosphate . This enzyme regulates the availability of thymidine and is therefore essential to nucleic acid metabolism. It promotes metastasis in Hepatocellular carcinoma (HCC) and may serve as a marker of poor prognosis in HCC, being a potential target for the treatment of HCC . Thymidine phosphorylase is also involved platelet activation and thrombosis leading to the development of cardiovascular diseases, thus, it has been suggested as a new target for cardiovascular disease treatment .
Hypothetical protein ST1625 (ST1625)
Type: Homologous_superfamily

Members of this superfamily are found in hypothetical proteins synthesised by the archaean Sulfolobus. Their exact function has not, as yet, been determined.
WD40-repeat-containing domain superfamily (WD40_repeat_dom_sf)
Type: Homologous_superfamily

This entry identifies a domain superfamily containing adjacent WD repeats. These WD repeats are located on β-sheets (blades) that fold into a higher order structure called β-propeller.

WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide. WD40 repeats usually assume a 7-8 bladed β-propeller fold, but proteins have been found with 4 to 16 repeated units, which also form a circularised β-propeller structure. WD-repeat proteins are a large family found in all eukaryotes and are implicated in a variety of functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. Repeated WD40 motifs act as a site for protein-protein or protein-DNA interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins . The specificity of the proteins is determined by the sequences outside the repeats themselves. Examples of such complexes are G proteins (beta subunit is a β-propeller), TAFII transcription factor, and E3 ubiquitin ligase . In Arabidopsis spp., several WD40-containing proteins act as key regulators of plant-specific developmental events.
Chemokine-binding M3 superfamily (M3_sf_vir)
Type: Homologous_superfamily

This entry represents a group of viral chemokine binding proteins, which bind with CC-chemokine MCP-1, acting as cytokine decoy receptors . For example, the murine herpesvirus decoy receptor M3 acts as an immune system saboteur by altering host anti-viral inflammatory repsonses. M3 adopts a structure consisting of two different β-sandwich domains of partial topological similarity to immunoglobulin-like folds.
Manganese/iron superoxide dismutase, N-terminal domain superfamily (Mn/Fe_SOD_N_sf)
Type: Homologous_superfamily

Superoxide dismutases (SODs) (

) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one . This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.

The structure of Fe/MnSODs can be divided into two domains, an N-terminal domain with an α-fold and α C-terminal domain with an α/β fold, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist . The structure of the C-terminal domain is of the α/β type, and consists of a three-stranded antiparallel β-sheet in the order 213, along with four helices in the arrangement α/β2/α/β/α2 .

This superfamily describes the N-terminal domain of manganese/iron superoxide dismutase.
Bacteriophage PRD1, P2, absorption protein superfamily (P2_sf)
Type: Homologous_superfamily

This entry represents absorption protein P2 (synonym: receptor-binding protein P2) from the bacteriophage PRD1. Absorption protein P2 is a multi-β-sheet protein whose complicated topology forms an elongated seahorse-shaped molecule with a distinct head, containing a pseudo-β propeller structure with approximate six-fold symmetry, and tail (β-sandwich). It is required for the attachment of the phage to the host conjugative DNA transfer complex. This is a poorly understood large transmembrane complex of unknown architecture, with at least 11 different proteins .
Spike S1 subunit, receptor binding domain superfamily, betacoronavirus (Spike_S1_RBD_sf_bCoV)
Type: Homologous_superfamily

The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface .

This superfamily represents the receptor-binding domain (RBD) of the Spike S1 subunit, which binds to angiotensin-converting enzyme 2 (ACE2) in respiratory syndrome coronavirus (SARS-CoV) , but not in some bat-derived coronaviruses (BatCoV) .

This domain is composed of a core and an external subdomain. During evolution, the core subdomain is structurally preserved, whereas the external subdomain folds into variant structures to engage different receptors. The most conserved part lies in the core-centre sheet that is composed of five antiparallel strands and functions as the scaffold of the core subdomain. Additional conserved elements include the core-centre helices and core-peripheral structures. Characteristic cysteine residues form three disulfide bonds in the core subdomain, further stabilizing the core structure from the interior .

The structure of this domain has three layers (α/β/α) with an antiparallel β-sheet of 5 strands.
Bacteriophage T4, Gp8 superfamily (Gp8_sf)
Type: Homologous_superfamily

Members of this superfamily of viral baseplate structural proteins adopt a structure consisting of a three-layer β-sandwich with two finger-like loops containing an α-helix at the opposite sides of the sandwich. The two peripheral, five-stranded, antiparallel β-sheets are stacked against the middle, four-stranded, antiparallel β-sheet. Attachment of this family of proteins to the baseplate during assembly creates a binding site for subsequent attachment of Gp6 .
C-type lysozyme inhibitor superfamily (MliC_sf)
Type: Homologous_superfamily

Lysozymes are ancient and important components of the innate immune system of animals that hydrolyse peptidoglycan, the major bacterial cell wall polymer. Various mechanisms have evolved by which bacteria can evade this bactericidal enzyme, one being the production of lysozyme inhibitors. MliC (membrane bound lysozyme inhibitor of c-type lysozyme) of E. coli and Pseudomonas aeruginosa, possess lysozyme inhibitory activity and confer increased lysozyme tolerance upon expression in E. coli . Structural analyses show that the invariant loop of MliC plays a crucial role in the inhibition of the lysozyme by its insertion into the active site cleft of the lysozyme, where the loop forms hydrogen and ionic bonds with the catalytic residues .

Interestingly, lipoprotein LprI has a C-terminal MliC domain, and has been identified only in virulence-associated mycobacterial strains, where it acts as a lysozyme inhibitor .
Aromatic amino acid monoxygenase, C-terminal domain superfamily (Aro-AA_hydroxylase_C_sf)
Type: Homologous_superfamily

Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes: the aromatic amino acid hydroxylase . Theseenzymes are structurally and functionally similar. The eukaryotic forms include a regulatory N-terminal domain, a catalytic domain and a C-terminal oligomerization motif. The eukaryotic enzymes are all homotetramers .

Three-dimensional structures have been determined for the three types of enzymes. The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function .

Enzymes that belong to the aromatic amino acid hydroxylase family are listed below:

Phenylalanine-4-hydroxylase (

) (PAH). Catalyzes the conversion of phenylalanine to tyrosine. In humans, deficiencies of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum , PAH is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa .

Tyrosine 3-hydroxylase (

) (TYH). Catalyzes the rate limiting step in catecholamine biosynthesis: the conversion of tyrosine to 3,4- dihydroxy-L-phenylalanine.

Tryptophan 5-hydroxylase (

) (TRH). Catalyzes the rate-limiting step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy- anthranilate.

This entry represents a domain containing the catalytic domain and the coiled-coil C-terminal oligomerization motif.
Oligosaccharyltransferase subunit ost4p superfamily (Ost4p_sf)
Type: Homologous_superfamily

Ost4 is a very short, approximately 30 residues, enzyme found from fungi to vertebrates. It is a member of the ER oligosaccaryltansferase complex,

, that catalyses the asparagine-linked glycosylation of proteins. It appears to be an integral membrane protein that mediates the en bloc transfer of a pre-assembled high-mannose oligosaccharide onto asparagine residues of nascent polypeptides as they enter the lumen of the rough endoplasmic reticulum.
Chagasin-like superfamily (Chagasin-like_sf)
Type: Homologous_superfamily

Chagasin is a reversible inhibitor of papain-like cysteine proteases . Chagasin has a β-barrel structure, which is a unique variant of the immunoglobulin fold with homology to human CD8alpha .
L-A virus major coat protein superfamily (Major_coat_LA-virus_sf)
Type: Homologous_superfamily

Members of this entry include the major coat protein of the Saccharomyces cerevisiae virus L-A (ScV-L-A) . The major coat protein is a large polypeptide without apparent domain division.
RNA synthesis protein NSP10 superfamily, coronavirus (NSP10_sf_CoV)
Type: Homologous_superfamily

Non-structural protein NSP10 is involved in RNA synthesis. It is synthesised as part of a replicase polyprotein, whose cleavage generates many non-structural proteins . NSP10 has a mixed α/β fold comprised of five α-helices contains, one 3(10)-helix, and three β-strands (

) and it is rich in cysteines, featuring two zinc fingers with Cx(2)-C-x(5)-H-x(6)-C and C-x(2)-C-x(7)-C-x-C motifs . Twelve identical subunits assemble to form a unique spherical dodecameric architecture, which is proposed to be a functional form of the ExoN/MTase coactivator domain

The small NSP10 protein is among the more conserved coronavirus proteins and a critical cofactor for activation of multiple replicative enzymes. It interacts with NSP14 and NSP16 acting as a scaffolding protein and regulating their respective exonuclease (ExoN) and ribose-2'-O-MTase (2'-O-MTase) activities , mediating the stabilization of the SAM binding pockets of NSP16 and NSP14. When binding to the N-terminal of NSP14, NSP10 allows the ExoN active site to adopt a stably closed conformation, allowing efficient hydrolysis of dsRNA . Efficient catalytic activity of NSP16 depends on heterodimerization with NSP10. The structure of the SARS-CoV-2 NSP10/NSP16 heterodimer revealed that it is extremely similar to that of its SARS-CoV-1 homologue .

One NSP10 residue, Tyr-96, is of particular interest. The aromatic nature of Tyr-96 plays a crucial role in the NSP10-NSP16 interaction and in the activation of the NSP16 2'-O-MTase activity as well as in the NSP10-NSP14 interaction. This residue is specific for SARS-CoV NSP10, and is a phenylalanine in other coronavirus homologues .
Bubble superfamily (Bubble_sf)
Type: Homologous_superfamily

Members of this superfamily of fungal proteins are functionally uncharacterised. They may act as toxins .