SII-SWORD/CoKE huggingface dataset:
DNA polymerase III, clamp loader complex, gamma/delta/delta subunit, C-terminal (DNA_pol3_clamp-load_cplx_C)
Type: Homologous_superfamily

The Escherichia coli DNA polymerase III gamma complex clamp loader assembles the ring-shaped beta sliding clamp onto DNA. The core polymerase is tethered to the template by beta, enabling progressive replication of the genome. The E. coli complex clamp loader contains five different subunits, clamp loading only requires 3 of these -the gamma, delta, delta' complex. Three gamma subunits, and one each of delta and delta', are arranged in a circle. Each subunit adopts the same chain topology, and folds into three domains. However, the relative orientation of these domains is different for each subunit. The carboxy-terminal domains provide the major subunit contacts of the pentamer, although other intersubunit contacts are present. The amino-terminal domains do not form a continuous circle. These domains are arranged in a highly asymmetric fashion, and appear to dangle under the carboxy-terminal pentamer 'umbrella' .
Di-copper centre-containing domain superfamily (Di-copper_centre_dom_sf)
Type: Homologous_superfamily

Copper active sites play a major role in biological dioxygen activation. Oxygen intermediates have been studied in detail for the proteins and enzymes involved in reversible O2 binding (hemocyanin), activation (tyrosinase), and four-electron reduction to water (multicopper oxidases). Tyrosinase binds two copper ions (CuA and CuB). Each of the two copper ions has been shown to be bound by three conserved histidine residues. The regions around these copper-binding ligands are well-conserved and also shared by some hemocyanins, which are copper-containing oxygen carriers from the hemolymph of many molluscs and arthropods .
Methyl-coenzyme M reductase, alpha/beta subunit, C-terminal (Me_CoM_Rdtase_asu/bsu_C)
Type: Homologous_superfamily

Methyl-coenzyme M reductase (MCR) catalyses the reduction of methyl-coenzyme M (CH3-SCoM) and coenzyme B (HS-CoB) to methane and the corresponding heterosulphide CoM-S-S-CoB (

), the final step in methane biosynthesis. This reaction proceeds under anaerobic conditions by methanogenic Archaea , and requires a nickel-porphinoid prosthetic group, coenzyme F430, which is in the EPR-detectable Ni(I) oxidation state in the active enzyme. Studies on a catalytically inactive enzyme aerobically co-crystallized with coenzyme M displayed a fully occupied coenzyme M-binding site with no alternate conformations. The binding of coenzyme M appears to induce specific conformational changes that suggests a molecular mechanism by which the enzyme ensures that methyl-coenzyme M enters the substrate channel prior to coenzyme B, as required by the active-site geometry .

MCR is a hexamer composed of 2 alpha, 2 beta, and 2 gamma subunits with two identical nickel porphinoid active sites, which form two long active site channels with F430 embedded at the bottom .

This superfamily represents the C-terminal domain of the alpha and beta subunits, which share a common structure. The C-terminal domain is a multi-helical bundle and contains a buried central helix.
Aminoacyl-tRNA synthetase, class I, anticodon-binding superfamily (aa_tRNA-synth_I_cd-bd_sf)
Type: Homologous_superfamily

Structurally, an α-helix-bundle anticodon-binding domain characterises the class Ia synthetases, whereas the class Ib synthetases, GlnRS and GluRS have distinct anticodon-binding domains. The anticodon-binding domain has a multi-helical structure, consisting of two all-alpha subdomains. The Rossmann-fold, made up of alternate α-helices and β-sheets involved in ATP binding in the extended conformation, and the anticodon-binding domains are connected by a β-α-α-β-α topology ('SC fold') domain that contains the class I specific KMSKS motif .

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .
Ribonucleotide reductase R1 subunit, N-terminal (RNR_R1-su_N)
Type: Homologous_superfamily

The large subunit (R1) of ribonucleotide reductase (RNR), is an essential enzyme required for DNA replication and DNA repair. In both Escherichia coli and higher organisms, the enzyme consists of two non-identical subunits, a dimer of an 85kDa protein, R1, and a dimer of a 45kDa protein, R2. Both subunits are essential for RNR enzyme activity - R1 contains, in the substrate binding site, the reducing active cysteine pair and R2 provides a catalytically essential organic radical. R1 is able to bind and reduce the four common ribonucleoside diphosphates. Substrate specificity is determined by nucleoside triphosphates binding to a protein site different from the active site and acting as allosteric effectors. Thus the presence of ATP makes the enzyme reduce CDP and UDP, dGTP favours ADP reduction and dTTP favours GDP reduction. dATP is a general inhibitor. This provides a mechanism for a balanced enzymatic production of building blocks for DNA synthesis .

This superfamily represents a mainly alpha domain found at the N terminus of the ribonucleotide reductase R1 subunit .
6-phosphogluconate dehydrogenase-like, C-terminal domain superfamily (6-PGluconate_DH-like_C_sf)
Type: Homologous_superfamily

6-phosphogluconate dehydrogenase (

) catalyses the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate with the concomitant reduction of NADP to NADPH. The metazoan 6PGDHs have a well-conserved glycine-serine rich sequence at the C terminus, which is lacking from bacterial enzymes and from those of the parasitic protozoan Trypanosoma brucei. The active dimer of the mammalian enzyme assembles with the C-terminal tail of one subunit threaded through the other, forming part of the substrate-binding site. The tail of T. brucei 6PGDH is shorter than that of the mammalian enzyme and its terminal residues associate tightly with the second monomer. The three-dimensional structure shows this generates additional interactions between the subunits close to the active site; the coenzyme-binding domain is thereby associated more tightly with the helical domain. Three residues, conserved in all other known sequences, are important in creating a salt bridge between monomers close to the substrate-binding site .

This domain is structurally similar to domains found in several different families, including those represented by mannitol 2-dehydrogenase, acetohydroxy acid isomeroreductase, short chain L-3-hydroxyacyl CoA dehydrogenase, UDP-glucose/GDP-mannose dehydrogenase (dimerisation domain), N-(1-D-carboxylethyl)-L-norvaline dehydrogenase, glycerol-3-phosphate dehydrogenase, and ketopantoate reductase (PanE).
Six-hairpin glycosidase superfamily (6-hairpin_glycosidase_sf)
Type: Homologous_superfamily

The six-hairpin glycoside transferase domain, with an α/α toroid fold, contains six α-hairpins arranged in closed circular array.

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'.
Chondroitin AC/alginate lyase (Chondroitin_lyas)
Type: Homologous_superfamily

Glycosaminoglycans (GAGs) are highly negatively charged polysaccharides, formed from disaccharide repeating units. For a number of bacterial species, including Flavobacterium heparinum synthesize GAG lyases, these enzymes are used to degrade and utilise glycosaminoglycans as a source of carbon in the bacterium's natural environment. In topological terms, the known structures of polysaccharide lyases fall within two protein fold families. Pectin and pectate lyases, as well as chondroitin lyase B belong to the right-handed parallel β-helix family and have the substrate-binding site in roughly the same topological location. The second topological family, all of which contain a domain consisting of an incomplete (α/α)5 toroid, includes chondroitin AC lyase family, and alginate lyase A1-III family from Sphingomonas species A1 .
Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid (Terpenoid_cyclase/PrenylTrfase)
Type: Homologous_superfamily

Protein prenyltransferases catalyse the transfer of the carbon moiety of C15 farnesyl pyrophosphate or geranylgeranyl pyrophosphate synthase to a conserved cysteine residue in a CaaX motif of protein and peptide substrates. The addition of a farnesyl group is required to anchor proteins to the cell membrane. In the 3D structure of a mammalian Ras farnesyltransferases (Ftase), both subunits are largely composed of α-helices. The α2 to α15 helices in the alpha subunit fold into a novel helical hairpin structure, resulting in a crescent-shape domain that envelopes part of the subunit. The 12 helices of the beta-subunit form an α-α barrel. Six additional helices connect the inner core of helices and form the outside of the helical barrel. A deep cleft surrounded by hydrophobic amino acids in the centre of the barrel is proposed as the FPP-binding pocket. A single Zn2+ ion is located at the junction between the hydrophilic surface groove near the subunit interface .

Terpenoid cyclases such as squalene cyclase, pentalenene synthase, 5-epi-aristolochene synthase, and trichodiene synthase are responsible for the synthesis of cholesterol, a hydrocarbon precursor of the pentalenolactone family of antibiotics, a precursor of the antifungal phytoalexin capsidiol, and the precursor of antibiotics and mycotoxins, respectively. In the structures of these three enzymes, the similar structural feature referred to as 'terpenoid synthase fold' with 10-12 mostly antiparallel α-helices is found, as also observed in protein prenyltransferases. The high structural similarity provides support for the hypothesis that the three families of prenyltransferases have related evolution despite their low sequence similarity .

Alpha-2-macroglobulin inhibit all four classes of proteinases by a unique 'trapping' mechanism in which the inhibitor undergoes global structural transformation to lead active proteases into its molecular cage. It also shows other functions related with the immune-cell function such as the binding of cytokines or the facilitation of cell migration .
Large ribosomal subunit protein bL12, oligomerization (Ribosomal_bL12_oligo)
Type: Domain

Large ribosomal subunit protein bL12 consists of two domains that are connected by a flexible region. The N-terminal domain is required for dimer formation and for anchoring the protein to the ribosome by binding to ribosomal protein L10, while the C-terminal domain is required for translation factors binding .

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 .
Virus capsid protein, alpha-helical (Virus_capsid_a-hlx_vir)
Type: Homologous_superfamily

The capsid of spherical viruses is built from a limited number of proteins and often displays icosahedral symmetry. Rotaviruses have a segmented double-stranded RNA genome enclosed in a complex capsid formed by three concentric protein layers. The proteins forming the capsid are VP2 (internal layer, with triangulation T = 1 and an asymmetric dimer in the icosahedral repeating unit), VP6 (intermediate layer, T = 13 symmetry), VP7 (external layer, T = 13) and VP4, which forms a spike inserted in the outermost two layers. The major capsid protein VP6 self-assembles into spherical or helical particles mainly depending upon pH. VP6 assemblies arise from different pickings of a unique dimer of trimers. The repeating unit of the helix contains a pair of trimers related by a radial dyad . The VP6 trimer is composed of two domains: a head (external) and a base (internal), leaving a central cavity, these are formed by a distal β-barrel domain and a proximal α-helical domain, which interact with the outer and inner layer of the virion, respectively .
Rho GTPase activation protein (Rho_GTPase_activation_prot)
Type: Homologous_superfamily

Proteins containing a RhoGAP (Rho GTPase Activating Protein) domain usually function to catalyse the hydrolysis of GTP that is bound to Rho, Rac and/or Cdc42, inactivating these regulators of the actin cytoskeleton. The 53 known human RhoGAP domain-containing proteins are the largest known group of Rho GTPase regulators and significantly outnumber the 21 Rho GTPases they presumably regulate. This excess of GAP proteins probably indicates complex regulation of the Rho GTPases and is consistent with the existence of almost as many (48) human Dbl domain-containing Rho GEFs that act antagonistically to the RhoGAP proteins by activating the Rho GTPases. Phylogenetic analysis offers evidence for frequent domain duplication and for duplication of the entire genes containing these GAP domains .
Ras-like guanine nucleotide exchange factor (Ras-like_GEF)
Type: Family

Small GTPases of the Ras family alternate between 2 conformations induced by the binding of either GTP or GDP. Guanine nucleotide exchange factors (GEFs) induce the dissociation of GDP to allow association of the more abundant GTP. The Ras-like family of small GTPases includes, among others, Ras, Rap1, R-ras, and Ral. The family is characterised by similarities in the effector domain. The Ras GTPase Rap1 is activated rapidly in response to activation of a variety of receptors. Rap1 activation is mediated by several second messengers, including calcium, diacylglycerol, and cAMP. GEFs have been identified that mediate these effects. One such GEF is Epac, an exchange protein directly activated by cAMP, which represents a novel cAMP-induced, protein kinase A-independent pathway .

This family also includes S. cerevisiae LTE1, a guanine nucleotide exchange factor for TEM1, a Ras-like protein that is a component of the mitotic exit network .
Lytic transglycosylase, superhelical U-shaped (Lytic_TGlycosylase_superhlx_U)
Type: Homologous_superfamily

Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with the concomitant formation of a 1,6-anhydrobond in the muramic acid residue. There are both soluble (Slt enzymes) and membrane-bound (Mlt enzymes) lytic transglycosylases that differ in size, sequence, activity, specificity and location. The multi-domain structure of the 70 Kd soluble lytic transglycosylase Slt70 is known . Slt70 has 3 distinct domains, each rich in α helices: an N-terminal superhelical U-shaped domain, a superhelical linker domain (L-domain,

), and a C-terminal catalytic domain (

). Both the U-and L-domain share a similar superhelical structure. These two domains are connected, and together form a closed ring with a large central hole; the catalytic domain is packed on top of, and interacts with, this ring. The catalytic domain has a lysosome-like fold.

This entry represents the superhelical U-domain, which contains 22 α helices packed in two curved layers, forming a right-handed superhelix with a U-shaped conformation.
ENTH/VHS (ENTH_VHS)
Type: Homologous_superfamily

This superfamily represents domains with a multi-helical, α-α 2-layered structural fold as found in: the ENTH domain of Epsin; the VHS domain of Hrs, Tom1, and ADP-ribosylation factors; the RPR domain of PCF11 protein; and the N-terminal domain of phosphoinositide-binding clathrin adaptor.

The epsin NH2-terminal homology (ENTH) domain is a membrane interacting module composed of a superhelix of α-helices. It is present at the NH2-terminus of proteins that often contain consensus sequences for binding to clathrin coat components and their accessory factors, and therefore function as endocytic adaptors. ENTH domain containing proteins have additional roles in signalling and actin regulation and may have yet other actions in the nucleus. The ENTH domain is structurally similar to the VHS domain.

The ENTH domain is approximately 150 amino acids long. The ENTH domain forms a compact globular structure, composed of eight α-helices connected by loops of varying length. Three helical hairpins that are stacked consecutively with a right-handed twist determine the general topology of the domain. This stacking gives the ENTH domain a rectangular appearance when viewed face on. The most highly conserved amino acids fall roughly into two classes: internal residues that are involved in packing and therefore are necessary for structural integrity, and solvent accessible residues that may be involved in protein-protein interactions .

VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking. The domain consists of eight helices arranged in a superhelix. The surface of the domain has two main features: a basic patch on one side due to several conserved positively charged residues on helix 3 and a negatively charged ridge on the opposite side, formed by residues on helix 2. Comparison of the two VHS domains and the ENTH domain reveals a conserved surface, composed of helices 2 and 4, that is utilised for protein-protein interactions. In addition, VHS domain-containing proteins are also often localized to membranes. It has therefore been suggested that the conserved positively charged surface of helix 3 in VHS and ENTH domains plays a role in membrane binding .
Bacteriophage T4, Gp59, helicase assembly protein (Phage_T4_Gp59)
Type: Family

The Bacteriophage T4 gene 59 helicase assembly protein (Gp59) is required for recombination-dependent DNA replication and repair, which is the predominant mode of DNA replication in the late stage of T4 infection. Gp59 accelerates the loading of the T4 gene 41 helicase during DNA synthesis by the T4 replication system in vitro. This protein binds to both T4 gene 41 helicase and T4 gene 32 single-stranded DNA binding protein, and to single and double-stranded DNA .

The structure of Gp59 helicase assembly protein reveals a novel α-helical bundle fold with two domains of similar size. Surface residues are predominantly basic (pI 9.37) with clusters of acidic residues but exposed hydrophobic residues suggest sites for potential contact with DNA and with other protein molecules . The N-terminal domain shares structural homology with the high mobility group (HMG) proteins from eukaryotic organisms and it has been suggested that it plays a role in duplex DNA binding ahead of the fork. The C-terminal domain interacts with the helicase (T4 gp41) and with SSB (single-stranded binding protein T4 gp32) .
Phospholipase C/P1 nuclease domain superfamily (PLipase_C/P1_nuclease_dom_sf)
Type: Homologous_superfamily

The enzymes belonging to this superfamily are involved in phosphate ester hydrolysis and contain a triad of closely spaced zinc ions at their active centres. Both families of enzymes hydrolyse phosphodiesters. Substrates for phospholipase C are phosphatidylinositol and phosphatidylcholine, while P1 nuclease is an endonuclease hydrolysing single stranded ribo-and deoxyribonucleotides. P1 nuclease also has activity as a phosphomonoesterase against 3'-terminal phosphates of nucleotides. The Zn ions in both enzymes form almost identical trinuclear sites .
L-Aspartase-like (L-Aspartase-like)
Type: Homologous_superfamily

The enzyme L-aspartate ammonia-lyase (aspartase) catalyses the reversible deamination of the amino acid L-aspartic acid, using a carbanion mechanism to produce fumaric acid and ammonium ion. Aspartases from different organisms show high sequence homology, and this homology extends to functionally related enzymes such as the class II fumarases, the argininosuccinate and adenylosuccinate lyases. The high-resolution structure of aspartase reveals a monomer that is composed of three domains oriented in an elongated S-shape . The central domain, comprised of five-helices, provides the subunit contacts in the functionally active tetramer. The active sites are located in clefts between the subunits and structural and mutagenic studies have identified several of the active site functional groups. A separate regulatory site has been identified. The substrate, aspartic acid, can also play the role of an activator, binding at this site along with a required divalent metal ion.
Isoprenoid synthase domain superfamily (Isoprenoid_synthase_dom_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in the isoprenoid synthase family , which is mostly all α-helical with a core bundle of anti-parallel α-helices .