SII-SWORD/CoKE huggingface dataset:
Serpin superfamily (Serpin_sf)
Type: Homologous_superfamily

Serpins (SERine Proteinase INhibitors) belong to MEROPS inhibitor family I4, clan ID. Most serpin family members are indeed serine protease inhibitors, but several have additional cross-class inhibition functions and inhibit cysteine protease family members such as the caspases and cathepsins . Others, such as ovalbumin, are incapable of protease inhibition and serve other functions .
DNA mismatch repair protein MutS, core domain superfamily (DNA_mismatch_repair_MutS_sf)
Type: Homologous_superfamily

Mismatch repair contributes to the overall fidelity of DNA replication and is essential for combating the adverse effects of damage to the genome. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutations or small insertion/deletion loops produced during DNA replication . MutS and MutL are involved in preventing recombination between partially homologous DNA sequences. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotides and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base . MutS can also collaborate with methyltransferases in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch . MutS exists as a dimer, where the two monomers have different conformations and form a heterodimer at the structural level . Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. Mismatch binding induces ATP uptake and a conformational change in the MutS protein, resulting in a clamp that translocates on DNA.

The core domain of MutS adopts a multi-helical structure comprised of two subdomains, which are interrupted by the clamp domain. Two of the helices in the core domain comprise the levers that extend towards the DNA. This domain is found associated with

,

,

and

. The aligned region corresponds with domain III, which is central to the structure of Thermus aquaticus MutS .
FAD/NAD(P)-binding domain superfamily (FAD/NAD-bd_sf)
Type: Homologous_superfamily

This FAD binding domain that characterises this superfamily has a nested NADH binding domain and is found in both class I and class II oxidoreductases and in FAD-dependent monooxygenases .

FAD flavoproteins belonging to the family of pyridine nucleotide-disulphide oxidoreductases (glutathione reductase, trypanothione reductase, lipoamide dehydrogenase, mercuric reductase, thioredoxin reductase, alkyl hydroperoxide reductase) share sequence similarity with a number of other flavoprotein oxidoreductases, in particular with ferredoxin-NAD+ reductases involved in oxidative metabolism of a variety of hydrocarbons (rubredoxin reductase, putidaredoxin reductase, terpredoxin reductase, ferredoxin-NAD+ reductase components of benzene 1,2-dioxygenase, toluene 1,2-dioxygenase, chlorobenzene dioxygenase, biphenyl dioxygenase), NADH oxidase and NADH peroxidase . Comparison of the crystal structures of human glutathione reductase and Escherichia coli thioredoxin reductase reveals different locations of their active sites, suggesting that the enzymes diverged from an ancestral FAD/NAD(P)H reductase and acquired their disulphide reductase activities independently .

Despite functional similarities, oxidoreductases of this family show no sequence similarity with adrenodoxin reductases and flavoprotein pyridine nucleotide cytochrome reductases (FPNCR) . Assuming that disulphide reductase activity emerged later, during divergent evolution, the family can be referred to as FAD-dependent pyridine nucleotide reductases, FADPNR.

To date, 3D structures of glutathione reductase , thioredoxin reductase , mercuric reductase , lipoamide dehydrogenase , trypanothione reductase and NADH peroxidase have been solved. The enzymes share similar tertiary structures based on a doubly-wound α/β fold, but the relative orientations of their FAD- and NAD(P)H-binding domains may vary significantly. By contrast with the FPNCR family, the folds of the FAD- and NAD(P)H-binding domains are similar, suggesting that the domains evolved by gene duplication .
mRNA decapping protein 2, Box A domain superfamily (DCP2_BoxA_sf)
Type: Homologous_superfamily

This superfamily represents the box A specific to mRNA decapping protein 2

, Dcp2, the catalytic subunit of the mRNA-decapping enzyme , which is found at the N-terminal of the NUDIX hydrolase domain

. Removal of the cap structure is mediated by the Dcp1-Dcp2 complex .

The Box A domain contains a four helices fold and an orthogonal array of two α-hairpins topology.
Urocanase superfamily (Urocanase_sf)
Type: Homologous_superfamily

Urocanase (also known as imidazolonepropionate hydrolase or urocanate hydratase) is the enzyme that catalyses the second step in the degradation of histidine, the hydration of urocanate into imidazolonepropionate:

urocanate + H
2
O = 4,5-dihydro-4-oxo-5-imidazolepropanoate

Urocanase is found in some bacteria (gene hutU) , in the liver of many vertebrates, and has also been found in the plant Trifolium repens (white clover). Urocanase is a protein of about 60 Kd, it binds tightly to NAD
+
and uses it as an electrophil cofactor. A conserved cysteine has been found to be important for the catalytic mechanism and could be involved in the binding of the NAD
+
.

This enzyme is a symmetric homodimer with tightly bound NAD+ cofactors. Each subunit consists of a typical NAD-binding domain inserted into a larger core domain that forms the dimer interface .

This entry also includes S-methyl thiourocanate hydratase which cannot use urocanate or thiourocanate as substrate and catalyses the conversion of S-methyl thiourocanate, to S-methyl-thiohydantoin-5-propanoate .
RRF superfamily (RRF_sf)
Type: Homologous_superfamily

The ribosome recycling factor or ribosome release factor (RRF) dissociates ribosomes from mRNA after termination of translation, and is essential for bacterial growth . Thus ribosomes are 'recycled' and ready for another round of protein synthesis.

Structurally, it is an L-shaped molecule .
Cell division protein ZapA-like superfamily (Cell_div_ZapA-like_sf)
Type: Homologous_superfamily

This entry represents a structural domain found in the cell division protein ZapA, as well as in related proteins. This domain has a core structure consisting of two layers alpha/beta, and has a long C-terminal helix that forms dimeric parallel and tetrameric antiparallel coiled coils . ZapA interacts with FtsZ, where FtsZ is part of a mid-cell cytokinetic structure termed the Z-ring that recruits a hierarchy of fission related proteins early in the bacterial cell cycle. ZapA drives the polymerisation and filament bundling of FtsZ, thereby contributing to the spatio-temporal tuning of the Z-ring.

The ZapA structure has a β(2)-α(2) fold with two layers (alpha/beta). It has a long C-terminal helix which forms dimeric parallel and tetrameric antiparallel coiled coils.
Adenylate kinase, active site lid domain superfamily (ADK_active_lid_dom_sf)
Type: Homologous_superfamily

Adenylate kinases (ADK;

) are phosphotransferases that catalyse the Mg-dependent reversible conversion of ATP and AMP to two molecules of ADP, an essential reaction for many processes in living cells. In large variants of adenylate kinase, the AMP and ATP substrates are buried in a domain that undergoes conformational changes from an open to a closed state when bound to substrate; the ligand is then contained within a highly specific environment required for catalysis. Adenylate kinase is a 3-domain protein consisting of a large central CORE domain flanked by a LID domain on one side and the AMP-binding NMPbind domain on the other . The LID domain binds ATP and covers the phosphates at the active site. The substrates first bind the CORE domain, followed by closure of the active site by the LID and NMPbind domains.

Comparisons of adenylate kinases have revealed a particular divergence in the active site lid. In some organisms, particularly the Gram-positive bacteria, residues in the lid domain have been mutated to cysteines and these cysteine residues (two CX(n)C motifs) are responsible for the binding of a zinc ion. The bound zinc ion in the lid domain is clearly structurally homologous to Zinc-finger domains. However, it is unclear whether the adenylate kinase lid is a novel zinc-finger DNA/RNA binding domain, or that the lid bound zinc serves a purely structural function .

The ADK LID domain structure has a Rubredoxin-like fold, which consists of a metal (zinc or iron)-bound fold.
Flagellar transcriptional activator FlhD superfamily (FlhD_sf)
Type: Homologous_superfamily

This superfamily consists of several bacterial flagellar transcriptional activator (FlhD) proteins. FlhD combines with FlhC to form a regulatory complex in Escherichia coli . This complex has been shown to be a global transcriptional regulator involved in many cellular processes as well as a flagellar transcriptional activator .

The FlhD protein is dimeric. The dimer is tightly coupled, with an intimate contact surface, implying that the dimer does not easily dissociate. The FlhD monomer is predominantly α-helical .
Alpha-L-arabinofuranosidase B, arabinose-binding domain superfamily (AbfB_ABD_sf)
Type: Homologous_superfamily

Alpha-L-arabinofuranosidase B (AkAbfB) comprises two domains: a catalytic domain and an arabinose-binding domain (ABD). This entry represents the ABD domain. ABD has a β-trefoil fold similar to that of carbohydrate-binding module (CBM) family 13 but also with a number of distinctive characteristics, suggesting that it could be classified into a new CBM family .
Phosphotyrosine protein phosphatase I superfamily (Ptyr_pPase_sf)
Type: Homologous_superfamily

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.

This entry represents the low molecular weight (LMW) protein-tyrosine phosphatases (or acid phosphatase), which act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates . The structure of a LMW PTPase has been solved by X-ray crystallography and is found to form a single structural domain. It belongs to the α/β class, with 6 α-helices and 4 β-strands forming a 3-layer α-β-α sandwich architecture.
NarG-like superfamily (NarG-like_sf)
Type: Homologous_superfamily

The superfamily includes the molybdo-bis(molybdopterin guanine dinucleotide) (Mo-bisMGD) cofactor-binding subunit NarG from nitrate reductase subunit. It also includes the homologous subunits from other oxidorectuases such as the coenzymeB--coenzymeM heterodisulphide reductase subunit E. Structurally NarG is composed of four α-β subdomains that are organised around the catalytic centre of the enzyme complex . Subdomains II and III are organised around the Mo-bisMGD cofactor.
Ecotin superfamily (Ecotin_sf)
Type: Homologous_superfamily

This entry represents proteinase inhibitors that belong to MEROPS inhibitor family I11, clan IN. Ecotins are dimeric periplasmic proteins from Escherichia coli and related Gram-negative bacteria that have been shown to be potent inhibitors of many trypsin-fold serine proteases of widely varying substrate specificity, which belong to MEROPS peptidase family S1 (

) . Phylogenetic analysis suggested that ecotin has an exogenous target, possibly neutrophil elastase. Ecotin from E. coli, Yersinia pestis, and Pseudomonas aeruginosa, all species that encounter the mammalian immune system inhibit neutrophil elastase strongly while ecotin from the plant pathogen Pantoea citrea inhibits neutrophil elastase 1000-fold less than the others .

They all potently inhibit pancreatic digestive peptidases trypsin and chymotrypsin, while showing more variable inhibition of the blood peptidases Factor Xa, thrombin, and urokinase-type plasminogen activator.

This entry represents the ecotin superfamily, consisting of 8 β strands organised in 2 sheets.
Portal protein Gp10 superfamily (Gp10_sf)
Type: Homologous_superfamily

This entry represents the upper collar protein (also known as portal protein Gp10) superfamily from various bacteriophage. The upper collar protein of Bacteriophage phi-29 is composed of twelve 36kDa subunits with 12-fold symmetry. It consists of two domains: an α-helical bundle domain and a β-barrel domain. This protein is located between the head and the tail of the bacteriophage and acts as the central component of a rotary motor that packages the genomic dsDNA into pre-formed proheads. This motor consists of the upper collar protein, surrounded by a 29-encoded, 174-base, RNA and a viral ATPase protein .
Attachment protein G3P, N-terminal domain superfamily (Attachment_G3P_N_sf)
Type: Homologous_superfamily

The G3P protein (also known as attachment protein or coat protein A) of filamentous phage such as M13, phage fd and phage f1, is an essential coat protein for the infection of Escherichia coli. The G3P protein consists of three domains: two N-terminal domains (N1 and N2) with a similar β-barrel fold, and a C-terminal domain . The N-terminal domains protrude from the phage surface, while the C-terminal domain acts as an anchor embedded in the phage coat, together forming a horseshoe-like structure . The G3P protein exists as 3-5 copies at the tip of the phage particle.
Pacifastin domain superfamily (Pacifastin_dom_sf)
Type: Homologous_superfamily

This entry represents the pacifastin domain superfamily.

Proteins containing this domain are proteinase inhibitors belonging to MEROPS inhibitor family I19 (clan IW) and sharing a pacifastin domain of ~35 residues, which contains a characteristic pattern of six conserved cysteine residues (C-x(9,12)-C-N-x-C-x-C-x(2,3)-G-x(3,6)-C-T-x(3)- C). The pacifastin domain consists of a twisted β-sheet composed of three antiparallel strands and stabilised by an identical pattern (C1-C4, C2-C6, C3-C5) of disulfide bridges .

This entry also contains the multidomain organization of SCO-spondin. The SCO-spondin protein is a special feature of the chordate phylum. This protein is expressed in the central nervous system (CNS) from the time a dorsal neural tube appears in the course of phylogenetical evolution .
DNA topoisomerase I, DNA binding, eukaryotic-type, N-terminal domain superfamily (TopoI_DNA-bd_euk_N_sf)
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 the N-terminal DNA-binding domain superfamily found in eukaryotic topoisomerase I, which is a 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 .

The structure of the N-terminal DNA-binding domain found in eukaryotic topoisomerase I has two domains. The first one has an α/β fold, while the other has an all alpha fold.
Poliovirus core protein 3a, soluble domain (P3A_soluble_dom)
Type: Homologous_superfamily

The 3A protein is found in positive-strand RNA viruses. It is a critical component of the poliovirus replication complex, and is also an inhibitor of host cell ER to Golgi transport.

This superfamily represents the soluble domain of poliovirus core protein 3a.
ATP synthase-coupling factor 6 superfamily, mitochondrial (ATP_synth_f6_sf_mt)
Type: Homologous_superfamily

This entry represents subunit F6 (or coupling factor 6) found in the F0 complex of F-ATPases in mitochondria. The F6 subunit is part of the peripheral stalk that links the F1 and F0 complexes together, and which acts as a stator to prevent certain subunits from rotating with the central rotary element. The peripheral stalk differs in subunit composition between mitochondrial, chloroplast and bacterial F-ATPases. In mitochondria, the peripheral stalk is composed of one copy each of subunits OSCP (oligomycin sensitivity conferral protein), F6, B and D . There is no homologue of subunit F6 in bacterial or chloroplast F-ATPase, whose peripheral stalks are composed of one copy of the delta subunit (homologous to OSCP), and two copies of subunit B in bacteria, or one copy each of subunits B and B' in chloroplasts and photosynthetic bacteria.

F6 has a flexible structure comprising two helices packed together through a loose hydrophobic core and connected by an unstructured linker and a hairpin topology .

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.
Thiamin phosphate synthase superfamily (ThiamineP_synth_sf)
Type: Homologous_superfamily

Thiamine phosphate synthase (TPS) catalyses the substitution of the pyrophosphate of 2-methyl-4-amino-5- hydroxymethylpyrimidine pyrophosphate by 4-methyl-5- (beta-hydroxyethyl)thiazole phosphate to yield thiamine phosphate in the thiamine biosynthesis pathway .

TenI, a protein from Bacillus subtilis that regulates the production of several extracellular enzymes by reducing alkaline protease production belongs to this group . While TenI shows high sequence similarity with thiamin phosphate synthase , the purified protein has no thiamin phosphate synthase activity. Instead, it is a thiazole tautomerase .
B-form DNA mimic Ocr (B-form_Ocr)
Type: Homologous_superfamily

Protein Ocr protects Bacteriophage T7 DNA from degradation and modification by the host restriction-modification complex . The structure of Ocr from T7 has shown that this protein mimics the size and shape of a bent DNA molecule, that binds to and completely occupies the DNA-binding sites of all known families of the complex type I DNA restriction enzymes which inhibits the restriction endonuclease activity . Ocr binds to bacterial RNA polymerase (RNAP) and competes with sigma factors resulting in host transcription inhibition and it also inhibits the host exclusion defense system BREX .