SII-SWORD/CoKE huggingface dataset:
Enolpyruvate transferase domain superfamily (Enolpyruvate_Tfrase_sf)
Type: Homologous_superfamily

5-enolpyruvylshikimate 3-phosphate synthase (EPSPS), also known as 3-phosphoshikimate 1-carboxyvinyltransferase, and UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), also known as UDP-N-acetylglucosamine 1-carboxyvinyltransferase, have both a unique three-dimensional topology and overall reaction mechanism in common . This entry represents the core domain superfamily of EPSPS and MurA, which transfers enolpryruvate from phosphoenolpyruvate to 3-phosphoshikimate and UDP-N-acetyl-alpha-D-glucosamine respectively.
Citrate synthase superfamily (Citrate_synthase_sf)
Type: Homologous_superfamily

Citrate synthase

is a member of a small family of enzymes that can directly form a carbon-carbon bond without the presence of metal ion cofactors. It catalyses the first reaction in the Krebs' cycle, namely the conversion of oxaloacetate and acetyl-coenzyme A into citrate and coenzyme A. This reaction is important for energy generation and for carbon assimilation. The reaction proceeds via a non-covalently bound citryl-coenzyme A intermediate in a 2-step process (aldol-Claisen condensation followed by the hydrolysis of citryl-CoA).

This entry represents types I and II citrate synthase enzymes, as well as the related enzymes 2-methylcitrate synthase and ATP citrate synthase. 2-methylcitrate (

) synthase catalyses the conversion of oxaloacetate and propanoyl-CoA into (2R,3S)-2-hydroxybutane-1,2,3-tricarboxylate and coenzyme A. This enzyme is induced during bacterial and fungal growth on propionate , while type II hexameric citrate synthase is constitutive . ATP citrate synthase (

) (also known as ATP citrate lyase) catalyses the MgATP-dependent, CoA-dependent cleavage of citrate into oxaloacetate and acetyl-CoA, a key step in the reductive tricarboxylic acid pathway of CO2 assimilation used by a variety of autotrophic bacteria and archaea to fix carbon dioxide . ATP citrate synthase is composed of two distinct subunits. In eukaryotes, ATP citrate synthase is a homotetramer of a single large polypeptide, and is used to produce cytosolic acetyl-CoA from mitochondrial produced citrate . This entry includes citrate synthase from Thermosulfidibacter takaii, which catalyses both citrate generation and citrate cleavage as it is part of a reversible tricarboxylic acid (TCA) cycle that can fix carbon dioxide autotrophically and may represent an ancestral mode of the conventional reductive TCA (rTCA) cycle .
3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily (PDEase_catalytic_dom_sf)
Type: Homologous_superfamily

The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.

PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma , Sildenafil for erectile dysfunction and Cilostazol for peripheral arterial occlusive disease , amongst others.

Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction . In rod cells, PDE is oligomeric, comprising an alpha-, a beta-and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.

This entry represents the C-terminal catalytic domain superfamily of PDE which is multihelical and can be divided into three subdomains.
Cytochrome c oxidase, subunit Vb superfamily (Cyt_c_oxidase_su5b_sf)
Type: Homologous_superfamily

Cytochrome c oxidase (

) is an oligomeric enzymatic complex which is a component of the respiratory chain complex and is involved in the transfer of electrons from cytochrome c to oxygen . In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane.

In eukaryotes, in addition to the three large subunits, I, II and III, that form the catalytic centre of the enzyme complex, there are a variable number of small polypeptidic subunits. One of these subunits, which is known as Vb in mammals, V in Dictyostelium discoideum (Slime mold) and IV in yeast, binds a zinc atom. The sequence of subunit Vb is well conserved and includes three conserved cysteines that coordinate the zinc ion . Two of these cysteines are clustered in the C-terminal section of the subunit.
Major capsid L1 (late) superfamily, Papillomavirus (Capsid_L1_sf_Papillomavir)
Type: Homologous_superfamily

This entry represents the major late capsid protein L1 from Papillomaviruses, such as Human papillomavirus (HPV) . Papillomaviruses are members of the papovavirus superfamily. More than 70 different types of papillomavirus have been discovered in humans, some of which have been shown to cause genital carcinomas and cutaneous warts . The viruses contain a circular dsDNA genome surrounded by an icosahedral capsid (non-enveloped). Two proteins are involved in capsid formation: a major (L1) and a minor (L2) protein, in the approximate proportion 95:5%. L1 forms a pentameric assembly unit of the viral shell in a manner that closely resembles VP1 from polyomaviruses. Intermolecular disulphide bonding holds the L1 capsid proteins together . L1 capsid proteins can bind via its nuclear localisation signal (NLS) to karyopherins Kapbeta(2) and Kapbeta(3) and inhibit the Kapbeta(2) and Kapbeta(3) nuclear import pathways during the productive phase of the viral life cycle . Surface loops on L1 pentamers contain sites of sequence variation between HPV types.
PUA domain superfamily (PUA_sf)
Type: Homologous_superfamily

The PUA (PseudoUridine synthase and Archaeosine transglycosylase) domain was named after the proteins in which it was first found . PUA is a highly conserved RNA-binding motif found in a wide range of archaeal, bacterial and eukaryotic proteins, including enzymes that catalyse tRNA and rRNA post-transcriptional modifications, proteins involved in ribosome biogenesis and translation, as well as in enzymes involved in proline biosynthesis . The structures of several PUA-RNA complexes reveal a common RNA recognition surface, but also some versatility in the way in which the motif binds to RNA . This domain has an α/β architecture consisting of six β-strands and two short α-helices . PUA motifs are involved in dyskeratosis congenita and cancer, pointing to links between RNA metabolism and human diseases .
Importin-alpha, importin-beta-binding domain superfamily (Importin-a_IBB_sf)
Type: Homologous_superfamily

This entry represents the N-terminal IBB domain superfamily of importin-alpha that contains the auto-regulatory region.

The exchange of macromolecules between the nucleus and cytoplasm takes place through nuclear pore complexes within the nuclear membrane. Active transport of large molecules through these pore complexes require carrier proteins, called karyopherins (importins and exportins), which shuttle between the two compartments.

Members of the importin-alpha (karyopherin-alpha) family can form heterodimers with importin-beta. As part of a heterodimer, importin-beta mediates interactions with the pore complex, while importin-alpha acts as an adaptor protein to bind the nuclear localisation signal (NLS) on the cargo through the classical NLS import of proteins. Proteins can contain one (monopartite) or two (bipartite) NLS motifs. Importin-alpha contains several armadillo (ARM) repeats, which produce a curving structure with two NLS-binding sites, a major one close to the N terminus and a minor one close to the C terminus.

Ran GTPase helps to control the unidirectional transfer of cargo. The cytoplasm contains primarily RanGDP and the nucleus RanGTP through the actions of RanGAP and RanGEF, respectively. In the nucleus, RanGTP binds to importin-beta within the importin/cargo complex, causing a conformational change in importin-beta that releases it from importin-alpha-bound cargo. The N-terminal importin-beta-binding (IBB) domain of importin-alpha contains an auto-regulatory region that mimics the NLS motif . The release of importin-beta frees the auto-regulatory region on importin-alpha to loop back and bind to the major NLS-binding site, causing the cargo to be released .
RimM, N-terminal domain superfamily (RimM_N_sf)
Type: Homologous_superfamily

The RimM protein is essential for efficient processing of 16S rRNA . It was shown to have affinity for free ribosomal 30S subunits but not for 30S subunits in the 70S ribosomes . RimM contains a characteristic N-terminal domain and a PRC-barrel C-terminal domain, linked by an unstructured region . The N-terminal domain folds into a closed β-barrel structure.
DNA Primase, CHC2-type zinc finger (DNA_primase_Znf_CHC2)
Type: Homologous_superfamily

DNA primase (

) is a nucleotidyltransferase which synthesizes the oligoribonucleotide primers required for DNA replication on the lagging strand of the replication fork. It can also prime the leading strand and has been implicated in cell division . Primases comprise three domains: a zinc-binding domain (N-terminal) that is responsible for template recognition, a polymerase domain (catalytic core), and a domain that interacts with the replicative helicase, DnaB (C-terminal).

This superfamily describes the zinc-binding domain of DNA primase, which belongs to the zinc ribbon type .
Chorismate mutase domain superfamily (CM_dom_sf)
Type: Homologous_superfamily

Chorismate mutase (

) catalyses the conversion of chorismate to prephenate in the pathway of tyrosine and phenylalanine biosynthesis. This enzyme is negatively regulated by tyrosine, tryptophan and phenylalanine . Prephenate dehydratase (

,

, PDT) catalyses the decarboxylation of prephenate into phenylpyruvate. In microorganisms PDT is involved in the terminal pathway of the biosynthesis of phenylalanine. In some bacteria, such as Escherichia coli, PDT is part of a bifunctional enzyme (P-protein) that also catalyzes the transformation of chorismate into prephenate (chorismate mutase) while in other bacteria it is a monofunctional enzyme. The sequence of monofunctional chorismate mutase aligns well with the N-terminal part of P-proteins .
Ribonuclease P/MRP subunit Rpp29 superfamily (RNase_P/MRP_Rpp29_sf)
Type: Homologous_superfamily

Ribonuclease P (Rnp) is a ubiquitous ribozyme that catalyzes a Mg2 -dependent hydrolysis to remove the 5'-leader sequence of precursor tRNA (pre-tRNA) in all three domains of life . In bacteria, the catalytic RNA (typically ~120kDa) is aided by a small protein cofactor (~14kDa) . Archaeal and eukaryote RNase P consist of a single RNA and archaeal RNase P has four or five proteins, while eukaryotic RNase P consists of 9 or 10 proteins. Eukaryotic and archaeal RNase P RNAs cooperatively function with protein subunits in catalysis .

This entry includes p29 subunit (also known as Rpp29 or Pop4) of the Ribonuclease P complex . Its homologues from eukaryotes are also a subunit of the RNase MRP complex. The structure of the RNase P subunit, Rpp29, from Methanobacterium thermoautotrophicum has been determined. Mth Rpp29 is a member of the oligonucleotide/oligosaccharide binding fold family. It contains a structured β-barrel core and unstructured N- and C-terminal extensions bearing several highly conserved amino acid residues that could be involved in RNA contacts in the protein-RNA complex . Rpp29 (

) catalyses the endonucleolytic cleavage of RNA, removing 5'-extranucleotides from tRNA precursor. It interacts with the Rpp25 and Pop5 subunits.
Deoxyhypusine synthase superfamily (Deoxyhypusine_synthase_sf)
Type: Homologous_superfamily

Eukaryotic initiation factor 5A (eIF-5A), now considered to be an elongation factor (see

), contains an unusual amino acid, hypusine [N epsilon-(4-aminobutyl-2-hydroxy)lysine]. The first step in the post-translational formation of hypusine is catalysed by the enzyme deoxyhypusine synthase (DS,

). The enzyme catalyses the following reaction:

Spermidine + [eIF-5A]-lysine = 1,3-diaminopropane + [eIF-5A]-deoxyhypusine

The modified version of eIF-5A, and DS, are required for eukaryotic cell proliferation . The structure is known for this enzyme in complex with its NAD
+
cofactor, it is a tetramer of four identical subunits arranged with 222 symmetry where each subunit contains a Rossmann fold .
Mitochondrial biogenesis AIM24 superfamily (AIM24_sf)
Type: Homologous_superfamily

In eukaryotes, proteins in this superfamily are involved in mitochondrial biogenesis . Its function in prokaryotes in unknown.
NrpR domain superfamily (NrpR_dom_sf)
Type: Homologous_superfamily

NrpR is an transcriptional repressor of nitrogen assimilation genes found primarily in Euryarchaeota . In the thermophilic archaeon Methanocaldococcus jannaschii it consists of a putative N-terminal winged helix-turn-helix (wHTH) domain used for DNA binding followed by two NrpR regulatory domains (NRD1 and NRD2) that sense and bind 2-oxoglutarate . In different organisms, NrpR proteins can vary on how many NrpR regulatory domains they contain and in their configuration. They can contain two NrpR domains, or one NrpR domain with or without the N-terminal HTH motif .

This superfamily describes the NRD domain, which consists of two halves. The helices from each half are located near the centre of the NRD domain forming an α-helical layer onto which the β-sheets are sandwiched from either side. A large cleft is formed between the two halves of the NRD regulatory domain .
Transglutaminase-like superfamily (Transglutaminase-like_sf)
Type: Homologous_superfamily

This domain superfamily is found in many proteins known to have transglutaminase activity, i.e. which cross-link proteins through an acyl-transfer reaction between the gamma-carboxamide group of peptide-bound glutamine and the ε-amino group of peptide-bound lysine, resulting in a ε-(gamma-glutamyl)lysine isopeptide bond. Tranglutaminases have been found in a diverse range of species, from bacteria through to mammals. The enzymes require calcium binding and their activity leads to post-translational modification of proteins through acyl-transfer reactions, involving peptidyl glutamine residues as acyl donors and a variety of primary amines as acyl acceptors, with the generation of proteinase resistant isopeptide bonds .
RNA-binding S4 domain superfamily (S4_RNA-bd_sf)
Type: Homologous_superfamily

The S4 domain is a small domain consisting of 60-65 amino acid residues that was detected in the bacterial small ribosomal subunit protein uS4, eukaryotic ribosomal uS4 (also known as S9), two families of pseudouridine synthases, a novel family of predicted RNA methylases, a yeast protein containing a pseudouridine synthetase and a deaminase domain, bacterial tyrosyl-tRNA synthetases, and a number of uncharacterised, small proteins that may be involved in translation regulation . The S4 domain probably mediates binding to RNA .
SRA-YDG superfamily (SRA-YDG_sf)
Type: Homologous_superfamily

This domain superfamily has been termed SRA-YDG, for SET and Ring finger Associated, and because of the conserved YDG motif within the domain. Further characteristics of the domain are the conservation of up to 13 evenly spaced glycine residues and a VRV(I/V)RG motif. The domain is mainly found in plants and animals and in bacteria. In animals, this domain is associated with the Np95-like ring finger protein and the related gene product Np97, which contains PHD and RING FINGER domains and which is an important determinant in cell cycle progression. Np95 is a chromatin-associated ubiquitin ligase, binding to histones is direct and shows a remarkable preference for histone H3 and its N-terminal tail. The SRA-YDG domain contained in Np95 is indispensable both for the interaction with histones and for chromatin binding
in vivo
. In plants the SRA-YDG domain is associated with the SET domain, found in a family of histone methyl transferases, and in bacteria it is found in association with HNH, a non-specific nuclease motif .
Picornavirus coat protein VP4 superfamily (Pico_P1A_sf)
Type: Homologous_superfamily

Picornaviruses are single-stranded RNA viruses. Processing of the viral polyprotein by picornains 3C and 2A generates capsid proteins VP0, VP1 and VP3, but VP0 undergoes an autolytic cleavage during virion assembly to generate capsid proteins VP2 and VP4 . The autolytic cleavage was originally thought to be the action of a serine-type peptidase, but from analogy with the similar autoproteolytic cleavages that are known for capsid proteins from nodaviruses (MEROPS peptidase family N1), tetraviruses (MEROPS peptidase family N2), picobirnaviruses (MEROPS peptidase family N5) and reoviruses (MEROPS peptidase family N7), it is more likely that VP0 is an asparagine-type peptidase; autocatalytic cleavage being promoted by cyclization of a conserved asparagine.
Metallocarboxypeptidase-like, propeptide (M14A-like_propep)
Type: Homologous_superfamily

The peptidases are synthesised as inactive molecules, zymogens, with propeptides that must be removed by proteolytic cleavage to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts .

This entry represents a propeptide associated with peptidases belonging to MEROPS peptidase family M14A. It is found in the carboxypeptidases A and B , and in fungal putative metallocarboxypeptidase Ecm14.
Iron hydrogenase, small subunit superfamily (Fe_hydrogenase_ssu_sf)
Type: Homologous_superfamily

Many microorganisms, such as methanogenic, acetogenic, nitrogen-fixing, photosynthetic, or sulphate-reducing bacteria, metabolise hydrogen. Hydrogen activation is mediated by a family of enzymes, termed hydrogenases, which either provide these organisms with reducing power from hydrogen oxidation, or act as electron sinks. There are two hydrogenases families that differ functionally from each other: NiFe hydrogenases tend to be more involved in hydrogen oxidation, while Iron-only FeFe (Fe only) hydrogenases in hydrogen production.

Fe only hydrogenases (

) can either be monomeric and cytoplasmic or heterodimeric and periplasmic, being involved in either hydrogen production or uptake, respectively. This entry represents the small subunit of the heterodimeric enzyme, which is comprised of alternating random coil and α helical structures that encompass the large subunit in a novel protein fold .

A domain homologous to the small subunit is found at the C terminus of iron-only hydrogenase-like protein 1 (IOP1) and IOP2 (also known as nuclear prelamin A recognition factor), two orthologue proteins found in mammalian cells. IOP1 has been shown to be involved in mammalian cytosolic Fe-S protein maturation .
Contactin-1, immunoglobulin domain 1 (Contactin-1_Ig1)
Type: Domain

Contactins are cell adhesion molecules that belong to the immunoglobulin superfamily and are involved in neural development . They usually consist of six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane .

Contactin-1 (CNTN1) is expressed by a diversity of neurons and contributes to the formation and function of neuronal connections . Contactin-1 regulates both myelin formation and organisation of nodal and paranodal domains in the central and peripheral nervous system . It plays a relevant role in cerebellar ontogenesis and cerebral cortex development . Contactin-1 contributes to the invasion and metastasis of several tumours . It is comprised of six immunoglobulin domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol.

This entry represents the first immunoglobulin (Ig) domain of contactin-1, which is located at the N-terminal end of the protein.
Methyl-coenzyme M reductase, gamma subunit superfamily (Me_CoM_Rdtase_gsu_sf)
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 entry represents the gamma subunit superfamily, which has a complex α-helical/β-sheet topology.
Methylpurine-DNA glycosylase superfamily (MPG_sf)
Type: Homologous_superfamily

Methylpurine-DNA glycosylase (MPG, or alkyladenine DNA glycosylase (AAG)) is a base excision-repair protein, catalyzing the first step in base excision repair by cleaving damaged DNA bases within double-stranded DNA to produce an abasic site. MPG bends DNA by intercalating between the base pairs, causing the damaged base to flip out of the double helix and into the enzyme active site for cleavage. It is responsible for the hydrolysis of the deoxyribose N-glycosidic bond, excising 3-methyladenine and 3-methylguanine from damaged DNA . Its action is induced by alkylating chemotherapeutics, as well as deaminated and lipid peroxidation-induced purine adducts . MPG without an N-terminal extension excises hypoxanthine with one-third of the efficiency of full-length MPG under similar conditions, suggesting that is function may largely be attributable to the N-terminal extension .

Although AAG represents one of six DNA glycosylase classes, it lacks the helix-hairpin-helix active site motif associated with other base excision repair glycosylases and is structurally distinct from them.
Proteasome activator PA28, N-terminal domain superfamily (PA28_N_sf)
Type: Homologous_superfamily

The specificity of the 20S proteasome, which degrades many intracellular proteins, is regulated by protein complexes that bind to one or both ends of the cylindrical proteasome structure. Proteasome activator 28 (PA28), also known as 11S regulator or REG, is one of these complexes. PA28 binds to the 20S proteasome and stimulates peptidase activity in and ATP-independent manner.

Three PA28 subunits that have been identified, PA28alpha (also known as proteasome activator complex subunit 1), PA28beta (also known as proteasome activator complex subunit 2) and PA28gamma (also known as proteasome activator complex subunit 3 or the Ki antigen), which share extensive sequence similarity, apart from a highly variable internal segment . PA28alpha and PA28beta form a ring shaped hexameric structure of alternating alpha and beta subunits. The catalytic properties of PA28alpha and PA28beta-activated proteosome are similar .

This entry represents a single-α helix N-terminal domain superfamily found in the proteasome activator 28 subunits.