SII-SWORD/CoKE huggingface dataset:
Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain (HMG_CoA_synt_C_dom)
Type: Domain

Hydroxymethylglutaryl-CoA synthase (

) catalyses the condensation of acetyl-CoA with acetoacetyl-CoA to produce HMG-CoA and CoA, the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA .

HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria . In vertebrates, there are two isozymes located in different subcellular compartments: a cytosolic form that is the starting point of the mevalonate pathway (leads to cholesterol and other sterolic and isoprenoid compounds), and a mitochondrial form responsible for ketone body biosynthesis. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi . In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes .

This entry represents the C-terminal domain of HMG-CoA synthase enzymes from both eukaryotes and prokaryotes.
Beta-ketoacyl-[acyl-carrier-protein] synthase III, C-terminal (ACP_syn_III_C)
Type: Domain

This domain is found in beta-ketoacyl-[acyl-carrier-protein] synthase III (also known as 3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III)

, the enzyme responsible for initiating the chain of reactions of the fatty acid synthase in plants and bacteria .
Replication factor C, C-terminal (Rep_factorC_C)
Type: Domain

This is the C-terminal domain of RFC (replication factor-C) protein of the clamp loader complex which binds to the DNA sliding clamp (proliferating cell nuclear antigen, PCNA). The five modules of RFC assemble into a right-handed spiral, which results in only three of the five RFC subunits (RFC-A, RFC-B and RFC-C) making contact with PCNA, leaving a wedge-shaped gap between RFC-E and the PCNA clamp-loader complex. The C-terminal is vital for the correct orientation of RFC-E with respect to RFC-A .
Pyridoxamine kinase/Phosphomethylpyrimidine kinase (PM/HMP-P_kinase-1)
Type: Domain

Enzymes in this family belong to the ribokinase superfamily. Pyridoxamine kinase

phosphorylates B6 vitamers and functions in a salvage pathway . Phosphomethylpyrimidine kinase

is part of the thiamine pyrophosphate (TPP) synthesis pathway. TPP is an essential cofactor for many enzymes .
GHMP kinase, C-terminal domain (GHMP_kinase_C_dom)
Type: Domain

This domain is found in homoserine kinases (

), galactokinases (

) and mevalonate kinases (

). These kinases make up the GHMP kinase superfamily of ATP-dependent enzymes . These enzymes are involved in the biosynthesis of isoprenes and amino acids as well as in carbohydrate metabolism. The C-terminal domain of homoserine kinase has a central α-β plait fold and an insertion of four helices, which, together with the N-terminal fold, create a novel nucleotide binding fold .
Beta-ketoacyl-[acyl-carrier-protein] synthase III, N-terminal (ACP_syn_III_N)
Type: Domain

Fatty acid synthesis (FAS) is a vital aspect of cellular physiology which can occur by two distinct pathways. The FAS I pathway, which generally only produces palmitate, is found in eukaryotes and is performed either by a single polypeptide which contains all the reaction centres needed to form a fatty acid, or by two polypeptides which interact to form a multifunctional complex. The FAS II pathway, which is capable of producing many different fatty acids, is found in mitochondria, bacteria, plants and parasites, and is performed by many distinct proteins, each of which catalyses a single step within the pathway. The large diversity of products generated by this pathway is possible because the acyl carrier protein (ACP) intermediates are diffusible entities that can be diverted into other biosynthetic pathways .

3-Oxoacyl-[acyl carrier protein (ACP)] synthase III catalyses the first condensation step within the FAS II pathway, using acetyl-CoA as the primer and malonyl-ACP as the acceptor, as shown below.

Acyl-[ACP] + malonyl-[ACP] = 3-oxoacyl-[ACP] + CO(2) + [ACP]

The oxoacyl-ACP formed by this reaction subsequently enters the elongation cycle, where the acyl chain is progressively lengthened by the combined activities of several enzymes.

The enzymes studied so far are homodimers, where each monomer consists of two domains (N-terminal and C-terminal) which are similar in structure, but not in sequence .

This entry represents a conserved region within the N-terminal domain.
Ketopantoate reductase, C-terminal domain (KPA_reductase)
Type: Domain

This is the C-terminal domain of 2-dehydropantoate 2-reductases also known as ketopantoate reductases . The reaction catalysed by this enzyme is: (R)-pantoate + NADP(+) = 2-dehydropantoate + NADPH. It is required for the synthesis of thiamine via the the alternative pyrimidine biosynthetic (APB) pathway .
Flaviviral glycoprotein E, central domain, subdomain 1 (Flav_gly_cen_dom_subdom1)
Type: Homologous_superfamily

Flaviviruses are small, enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include
Yellow fever virus (YFV),
West Nile virus (WNV),
Tick-borne encephalitis virus,
Japanese encephalitis virus (JE) and
Dengue virus 2 viruses . Flaviviruses consist of three structural proteins: the core nucleocapsid protein C (

), and the envelope glycoproteins M (

) and E. Glycoprotein E is a class II viral fusion protein that mediates both receptor binding and fusion. Class II viral fusion proteins are found in flaviviruses and alphaviruses, and are structurally distinct from class I fusion proteins from influenza virus and HIV.

Glycoprotein E is comprised of three domains: domain I (dimerisation domain) is an 8-stranded β barrel, domain II (central domain) is an elongated domain composed of twelve β strands and two α helices, and domain III (immunoglobulin-like domain) is an IgC-like module with ten β strands. Domains I and II are intertwined . Domain II can be divided into two structural components, both of which comprise α-β sandwich folds. This entry represents subdomain 1 of domain II, the central domain.

The glycoprotein E dimers on the viral surface re-cluster irreversibly into fusion-competent trimers upon exposure to low pH, as found in the acidic environment of the endosome. The formation of trimers results in a conformational change in the hinge region of domain II, a key structural element that opens a ligand-binding hydrophobic pocket at the interface between domains I and II. The conformational change results in the exposure of a fusion peptide loop at the tip of domain II, which is required in the fusion step to drive the cellular and viral membranes together by inserting into the membrane .
Flaviviral glycoprotein E, central domain, subdomain 2 (GlyE_cen_dom_subdom2)
Type: Homologous_superfamily

Flaviviruses are small, enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include
Yellow fever virus (YFV),
West Nile virus (WNV),
Tick-borne encephalitis virus,
Japanese encephalitis virus (JE) and
Dengue virus 2 viruses . Flaviviruses consist of three structural proteins: the core nucleocapsid protein C (

), and the envelope glycoproteins M (

) and E. Glycoprotein E is a class II viral fusion protein that mediates both receptor binding and fusion. Class II viral fusion proteins are found in flaviviruses and alphaviruses, and are structurally distinct from class I fusion proteins from influenza virus and HIV.

Glycoprotein E is comprised of three domains: domain I (dimerisation domain) is an 8-stranded β barrel, domain II (central domain) is an elongated domain composed of twelve β strands and two α helices, and domain III (immunoglobulin-like domain) is an IgC-like module with ten β strands. Domains I and II are intertwined . Domain II can be divided into two structural components, both of which comprise α-β sandwich folds. This entry represents subdomain 2 of domain II, the central domain.

The glycoprotein E dimers on the viral surface re-cluster irreversibly into fusion-competent trimers upon exposure to low pH, as found in the acidic environment of the endosome. The formation of trimers results in a conformational change in the hinge region of domain II, a key structural element that opens a ligand-binding hydrophobic pocket at the interface between domains I and II. The conformational change results in the exposure of a fusion peptide loop at the tip of domain II, which is required in the fusion step to drive the cellular and viral membranes together by inserting into the membrane .
DNA topoisomerase, type IIA, alpha-helical domain superfamily (Topo_IIA_A_a_sf)
Type: Homologous_superfamily

Type IIA topoisomerases include the enzymes DNA gyrase, eukaryotic topoisomerase II (topo II), and bacterial topoisomerase IV (topo IV). Type IIA topoisomerases together manage chromosome integrity and topology in cells. Topoisomerase II (called gyrase in bacteria) primarily introduces negative supercoils into DNA. In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively; this topoisomerase II forms a homodimer that is equivalent to the bacterial heterotetramer. There are four functional domains in topoisomerase II: domain 1 (N-terminal of gyrB) is an ATPase, domain 2 (C-terminal of gyrB) is responsible for subunit interactions (differs between eukaryotic and bacterial enzymes), domain 3 (N-terminal of gyrA) is responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges, and domain 4 (C-terminal of gyrA) is able to non-specifically bind DNA .

Topoisomerase IV primarily decatenates DNA and relaxes positive supercoils, which is important in bacteria, where the circular chromosome becomes catenated, or linked, during replication . Topoisomerase IV consists of two polypeptide subunits, parE and parC, where parC is homologous to gyrA and parE is homologous to gyrB.

This superfamily represents a mainly α helical subdomain of eukaryotic topoisomerase II domain 3, also found in subunit A (gyrA and parC) of bacterial gyrase and topoisomerase IV.
DNA topoisomerase, type IIA, domain A, alpha-beta (Topo_IIA_A/C_ab)
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 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 .

Type IIA topoisomerases together manage chromosome integrity and topology in cells. Topoisomerase II (called gyrase in bacteria) primarily introduces negative supercoils into DNA. In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively; this topoisomerase II forms a homodimer that is equivalent to the bacterial heterotetramer. There are four functional domains in topoisomerase II: domain 1 (N-terminal of gyrB) is an ATPase, domain 2 (C-terminal of gyrB) is responsible for subunit interactions (differs between eukaryotic and bacterial enzymes), domain 3 (N-terminal of gyrA) is responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges, and domain 4 (C-terminal of gyrA) is able to non-specifically bind DNA .

Topoisomerase IV primarily decatenates DNA and relaxes positive supercoils, which is important in bacteria, where the circular chromosome becomes catenated, or linked, during replication . Topoisomerase IV consists of two polypeptide subunits, parE and parC, where parC is homologous to gyrA and parE is homologous to gyrB.

This superfamily represents the α-β domain of subunit A (gyrA and parC) of bacterial gyrase and topoisomerase IV, and the equivalent C-terminal region in eukaryotic topoisomerase II composed of a single polypeptide.
DNA topoisomerase, type IIA, subunit B, C-terminal (Topo_IIA_B_C)
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 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 .

Type IIA topoisomerases together manage chromosome integrity and topology in cells. Topoisomerase II (called gyrase in bacteria) primarily introduces negative supercoils into DNA. In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively; this topoisomerase II forms a homodimer that is equivalent to the bacterial heterotetramer. There are four functional domains in topoisomerase II: domain 1 (N-terminal of gyrB) is an ATPase, domain 2 (C-terminal of gyrB) is responsible for subunit interactions (differs between eukaryotic and bacterial enzymes), domain 3 (N-terminal of gyrA) is responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges, and domain 4 (C-terminal of gyrA) is able to non-specifically bind DNA .

Topoisomerase IV primarily decatenates DNA and relaxes positive supercoils, which is important in bacteria, where the circular chromosome becomes catenated, or linked, during replication . Topoisomerase IV consists of two polypeptide subunits, parE and parC, where parC is homologous to gyrA and parE is homologous to gyrB.

This superfamily represents the C-terminal domain of subunit B (gyrB and parE) of bacterial gyrase and topoisomerase IV, and the equivalent region in eukaryotic topoisomerase II composed of a single polypeptide.
DNA topoisomerase, type IIA-like domain superfamily (Topo_IIA-like_dom_sf)
Type: Homologous_superfamily

Type IIA topoisomerases together manage chromosome integrity and topology in cells. Topoisomerase II (called gyrase in bacteria) primarily introduces negative supercoils into DNA. In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively; this topoisomerase II forms a homodimer that is equivalent to the bacterial heterotetramer. There are four functional domains in topoisomerase II: domain 1 (N-terminal of gyrB) is an ATPase, domain 2 (C-terminal of gyrB) is responsible for subunit interactions (differs between eukaryotic and bacterial enzymes), domain 3 (N-terminal of gyrA) is responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges, and domain 4 (C-terminal of gyrA) is able to non-specifically bind DNA .

Topoisomerase IV primarily decatenates DNA and relaxes positive supercoils, which is important in bacteria, where the circular chromosome becomes catenated, or linked, during replication . Topoisomerase IV consists of two polypeptide subunits, parE and parC, where parC is homologous to gyrA and parE is homologous to gyrB.

This superfamily represents the C-terminal of subunit B (gyrB and parE) and the N-terminal of subunit A (gyrA and parC) of bacterial gyrase and topoisomerase IV, and the equivalent region in eukaryotic topoisomerase II composed of a single polypeptide.
Sterile alpha motif/pointed domain superfamily (SAM/pointed_sf)
Type: Homologous_superfamily

Sterile alpha motif (SAM) domains are known to be involved in diverse protein-protein interactions, associating with both SAM-containing and non-SAM-containing proteins pathway . SAM domains exhibit a conserved structure, consisting of a 4-5-helical bundle of two orthogonally packed α-hairpins. However SAM domains display a diversity of function, being involved in interactions with proteins, DNA and RNA . The name sterile alpha motif arose from its presence in proteins that are essential for yeast sexual differentiation. The SAM domain has had various names, including SPM, PTN (pointed), SEP (yeast sterility, Ets-related, PcG proteins), NCR (N-terminal conserved region) and HLH (helix-loop-helix) domain, all of which are related and can be classified as SAM domains.

SAM domains occur in eukaryotic and in some bacterial proteins. Structures have been determined for several proteins that contain SAM domains, including Ets-1 transcription factor, which plays a role in the development and invasion of tumour cells by regulating the expression of matrix-degrading proteases ; Etv6 transcription factor, gene rearrangements of which have been demonstrated in several malignancies ; EphA4 receptor tyrosine kinase, which is believed to be important for the correct localization of a motoneuron pool to a specific position in the spinal cord ; EphB2 receptor, which is involved in spine morphogenesis via intersectin, Cdc42 and N-Wasp ; p73, a p53 homologue involved in neuronal development ; and polyhomeotic, which is a member of the Polycomb group of genes (Pc-G) required for the maintenance of the spatial expression pattern of homeotic genes .
Integrase-like, catalytic domain superfamily (Integrase-like_cat_sf)
Type: Homologous_superfamily

Phage integrases are enzymes that mediate unidirectional site-specific recombination between two DNA recognition sequences, the phage attachment site, attP, and the bacterial attachment site, attB . Integrases may be grouped into two major families, the tyrosine recombinases and the serine recombinases, based on their mode of catalysis. Tyrosine family integrases, such as lambda integrase, utilise a catalytic tyrosine to mediate strand cleavage, tend to recognise longer attP sequences, and require other proteins encoded by the phage or the host bacteria.

The 356 amino acid lambda integrase consists of two domains: an N-terminal domain that includes residues 1-64 and is responsible for binding the arm-type sites of attP, and a C-terminal domain (CTD) that binds the lower affinity core-type sites and contains the catalytic site. The CTD can be further divided into the core-type binding domain (residues 65-169) and the catalytic core domain (170-356), the later representing this entry. The catalytic core adopts an alpha3-beta3-alpha4 fold, where one side of the β sheet is exposed.

The recombinases Cre from phage P1, XerD from Escherichia coli and Flp from yeast are members of the tyrosine recombinase family, and have a two-domain motif resembling that of lambda integrase, as well as sharing a conserved binding mechanism . The structural fold of their catalytic core domains resemble that of Lambda integrase.
Cyclin-like domain (Cyclin-like_dom)
Type: Domain

This cyclin-like domain is found in cyclins, but it is also found as the core domain in transcription factor IIB (TFIIB) and in the retinoblastoma tumour suppressor . It consists of a duplication of a fold consisting of 5 helices, one of them surrounded by the others.
DNA recombination and repair protein RecA (DNA_recomb/repair_RecA)
Type: Family

The recA gene product is a multifunctional enzyme that plays a role in homologous recombination, DNA repair and induction of the SOS response . In homologous recombination, the protein functions as a DNA-dependent ATPase, promoting synapsis, heteroduplex formation and strand exchange between homologous DNAs . RecA also acts as a protease cofactor that promotes autodigestion of the lexA product and phage repressors. The proteolytic inactivation of the lexA repressor by an activated form of recA may cause a derepression of the 20 or so genes involved in the SOS response, which regulates DNA repair, induced mutagenesis, delayed cell division and prophage induction in response to DNA damage .

RecA is a protein of about 350 amino-acid residues. Its sequence is very well conserved among eubacterial species. It is also found in the chloroplast of plants . RecA-like proteins are found in archaea and diverse eukaryotic organisms, like fission yeast, mouse or human. In the filament visualised by X-ray crystallography, β-strand 3, the loop C-terminal to β-strand 2, and α-helix D of the core domain form one surface that packs against α-helix A and β-strand 0 (the N-terminal domain) of an adjacent monomer during polymerisation . The core ATP-binding site domain is well conserved, with 14 invariant residues. It contains the nucleotide binding loop between β-strand 1 and α-helix C. The Escherichia coli sequence GPESSGKT matches the consensus sequence of amino acids (G/A)XXXXGK(T/S) for the Walker A box (also referred to as the P-loop) found in a number of nucleoside triphosphate (NTP)-binding proteins. Another nucleotide binding motif, the Walker B box is found at β-strand 4 in the RecA structure. The Walker B box is characterised by four hydrophobic amino acids followed by an acidic residue (usually aspartate). Nucleotide specificity and additional ATP binding interactions are contributed by the amino acid residues at β-strand 2 and the loop C-terminal to that strand, all of which are greater than 90% conserved among bacterial RecA proteins.