SII-SWORD/CoKE huggingface dataset:
SH3 domain (SH3_domain)
Type: Domain

SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues . They are found in a great variety of intracellular or membrane-associated proteins for example, in a variety of proteins with enzymatic activity, in adaptor proteins, such as fodrin and yeast actin binding protein ABP-1.

The SH3 domain has a characteristic fold which consists of five or six β-strands arranged as two tightly packed anti-parallel β-sheets. The linker regions may contain short helices. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes .

The crystal structure of the SH3 domain of the cytoskeletal protein spectrin, and the solution structures of SH3 domains of phospholipase C (PLC-y) and phosphatidylinositol 3-kinase p85 alpha-subunit, have been determined . In spite of relatively limited sequence similarity, their overall structures are similar. The domains belong to the α+β structural class, with five to eight β-strands forming 2 tightly-packed, anti-parallel β-sheets arranged in a barrel-like structure, and intervening loops sometimes forming helices. Conserved aliphatic and aromatic residues form a hydrophobic core (A11, L23, A29, V34, W42, L52 and V59 in PLC-y ) and a hydrophobic pocket on the molecular surface (L12, F13, W53 and P55 in PLC-y). The conserved core is believed to stabilise the fold, while the pocket is thought to serve as a binding site for target proteins. Conserved carboxylic amino acids located in the loops, on the periphery of the pocket (D14 and E22), may be involved in protein-protein interactions via proline-rich regions. The N- and C-terminal are packed in close proximity, indicating that they are independent structural modules.
MoaB/Mog domain (MoaB/Mog_dom)
Type: Domain

MoaB/Mog domain, also known as Cnx1G domain, is found in the bacterial molybdenum cofactor (Moco) biosynthesis protein MoaB/Mog and N-terminal of the eukaryotic MoCF biosynthesis proteins, such as the Drosophila protein cinnamon, the Arabidopsis protein cnx1 and the mammal protein gephyrin . These proteins are involved in the final steps of Moco synthesis. In E. coli two proteins, MogA and MoeA are essential for Mo insertion into molybdopterin, while in plants and animals one fusion protein with two domains (G and E domains) fulfils this function. The G domain of Cnx1 and gephyrin shares similarity with MoaB/Mog, while their E domain displays similarities to the sulfurtransferase rhodanese (homologous to E. coli MoeA/chlE) . Structurally, MogA is folded into a compact molecule with α/β/α architecture and forms a trimer . The Cnx1G domain has been shown to bind molybdopterin .

This domain is also found in N-terminal of the FAD synthases belonging to a family that catalyses the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme . CinA from Thermus thermophilus is shown to have both nicotinamide mononucleotide deamidase and ADP-ribose pyrophosphatase activities, with ADP-ribose pyrophosphatase activity attributed to the N-terminal domain .
TusA-like domain (TusA-like)
Type: Domain

The structure of TusA (also known YhhP and SirA) consists of an α/β sandwich with a β-α-β-α-β(2) fold, comprising a mixed four-stranded β-sheet stacked against two α-helices, both of which are nearly parallel to the strands of the β-sheet . Several uncharacterised bacterial proteins (73 to 81 amino-acid residues in length) that contain a well-conserved region in their N-terminal region show structural similarity to the TusA protein, including the E. coli protein YedF (

), and other members of the UPF0033 family.

NOTE: TusA was previously known as SirA, but should not be confused with the sporulation inhibitor of replication protein SirA (

) or with the LuxR/UhpA family response regulator

, also known as SirA.
NADH:ubiquinone/plastoquinone oxidoreductase, chain 6 (NADH_UbQ/plastoQ_OxRdtase_su6)
Type: Family

This entry represents chain 6 from NADH:ubiquinone oxidoreductase and NADH-plastoquinone oxidoreductase. Bacterial proton-translocating NADH-quinone oxidoreductase (NDH-1) is composed of 14 different subunits. The chain belonging to this family is a subunit that constitutes the membrane sector of the complex. It reduces ubiquinone to ubiquinol utilising NADH. Plant chloroplastic NADH-plastoquinone oxidoreductase reduces plastoquinone to plastoquinol. Mitochondrial NADH-ubiquinone oxidoreductase from a variety of sources reduces ubiquinone to ubiquinol.
GPCR, family 3, metabotropic glutamate receptor 2 (GPCR_3_mGluR2)
Type: Family

The mRNA for GRM2 is widespread in the brain, with a unique distribution; it is found in high levels in neurons in olfactory bulb, cerebral cortex, cerebellum Golgi cells, and dentate gyrus granule cells. GRM2 inhibits adenylyl cyclase
through a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class; the receptor has also been reported to cause a weak stimulation of phosphoinositide metabolism. It may mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization .

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

The metabotropic glutamate receptors are functionally and pharmacologically distinct from the ionotropic glutamate receptors. They are coupled to G-proteins and stimulate the inositol phosphate/Ca
2+
intracellular signalling pathway . At least eight sub-types of metabotropic receptor (GRM1-8) have been identified in cloning studies. The sub-types differ in their agonist pharmacology and signal transduction pathways.
Penicillin-binding protein, transpeptidase (PCN-bd_Tpept)
Type: Domain

This signature identifies a large group of proteins, which include:

Beta-lactamase precursor (

, penicillinase)

Peptidoglycan synthetase ftsI (

, peptidoglycan glycosyltransferase 3)

Methicillin resistance mecR1 protein

Methicillin resistance blaR1 protein

The large number of penicillin binding proteins, which are represented in this group of sequences, are responsible for the final stages of peptidoglycan biosynthesis for cell wall formation. The proteins synthesise cross-linked peptidoglycan from lipid intermediates, and contain a penicillin-sensitive transpeptidase carboxy-terminal domain. The active site serine (residue 337 in

) is conserved in all members of this family .

MecR1 and BlaR1 are metallopeptidases belonging to MEROPS peptidase family M56, clan M-. BlaR1 and MecR1 cleave their cognate transcriptional repressors BlaI and MecI, respectively, activating the synthesis of MecA.

MecR1 is present in Staphylococcus aureus and Staphylococcus sciuri, whereas BlaR1 (also known as BlaR, PenR1, or PenJ) has been found in Bacillus licheniformis, Staphylococcus epidermidis, Staphylococcus haemolyticus, and several S. aureus strains. These proteins are either plasmid-encoded, chromosomal, or transposon-mediated. MecR1/BlaR1 proteins are made up by homologous N-terminal 330-residue transmembrane metallopeptidase domains linked to extracellular 260-residue homologous PBP-like penicillin sensor moieties.
Aspartic peptidase A1 (Aspartic_peptidase_A1)
Type: Family

Peptidase family A1, also known as the pepsin family, contains peptidases with bilobed structures . The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain . The active site is formed from an aspartic acid residue from each domain. Each aspartic acid occurs within a motif with the sequence D(T/S)G(T/S). Exceptionally, in the histoaspactic peptidase from Plasmodium falciparum, one of the Asp residues is replaced by His . A third essential residue, Tyr or Phe, is found on the N-terminal domain only in a β-hairpin loop known as the "flap"; this residue is important for substrate binding, and most members of the family have a preference for a hydrophobic residue in the S1 substrate binding pocket. Most members of the family are active at acidic pH, but renin is unusually active at neutral pH. Family A1 peptidases are found predominantly in eukaryotes (but examples are known from bacteria ). Currently known eukaryotic aspartyl peptidases and homologues include the following:

Vertebrate gastric pepsins A (

), gastricsin (

, also known pepsin C), chymosin (

; formerly known as rennin), and cathepsin E (

). Pepsin A is widely used in protein sequencing because of its limited and predictable specificity. Chymosin is used to clot milk for cheese making.

Lysosomal cathepsin D (

).

Renin (

) which functions in control of blood pressure by generating angiotensin I from angiotensinogen in the plasma.

Memapsins 1 (

; also known as BACE 2) and 2 (

; also known as BACE) are membrane-bound and are able to perform one of the two cleavages (the beta-cleavage, hence they are also known as beta-secretases) in the beta-amyloid precursor to release the the amyloid-beta peptide, which accumulates in the plaques of Alzheimer's disease patients.

Fungal peptidases such as aspergillopepsin A (

), candidapepsin (

), mucorpepsin (

; also known as
Mucor
rennin), endothiapepsin (

), polyporopepsin (

), and rhizopuspepsin (

) are secreted for sapprophytic protein digestion.

Fungal saccharopepsin (

) (proteinase A) (gene PEP4) is implicated in post-translational regulation of vacuolar hydrolases.

Yeast barrierpepsin (

) (gene BAR1); a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone.

Fission yeast Sxa1 may be involved in degrading or processing the mating pheromones .

In plants, phytepsin (

) degrades seed storage proteins and nepenthesin (EC 3.4.23.12) from a pitcher plant digests insect proteins. Also are included Aspartic proteinase 36 and Aspartic proteinase 39, which contribute to pollen and ovule development and have an important role in plant development in Arabidopsis .

Plasmepsins (

and

) from Plasmodium species are important for the degradation of host haemoglobin.

Non-peptidase homologues where one or more active site residues have been replaced, include mammalian pregnancy-associated glycoproteins, an allergen from a cockroach, and a xylanase inhibitor .
Hepadnaviral P protein, C-terminal (DNApol_viral_C)
Type: Domain

This domain is at the C terminus of hepatitis B-type viruses P proteins and represents a functional domain that controls the RNase H activities of the protein. The domain is always associated with

and

.
Sodium:alanine symporter (Na/Ala_symport)
Type: Family

Sodium symporters can be divided by sequence and functional similarity into various groups. One such group is the sodium/alanine symporter family, the members of which transport alanine in association with sodium ions.

These transporters have between 10-14 transmembrane (TM) helices , characterised by a five or seven transmembrane helix inverted-topology repeat motif, forming a channel or pore through the cytoplasmic membrane, the interior face being hydrophilic to allow the passage of alanine molecules and sodium ions . This family is restricted to the bacteria and archaea, examples are the alanine carrier protein from the Bacillus PS3 (Thermophilic bacterium PS-3); the sodium/alanine symporter AgcS from Methanococcus maripaludis , the D-alanine/glycine permease from Pseudoalteromonas haloplanktis (Alteromonas haloplanktis); and the hypothetical protein yaaJ from Escherichia coli.
Annexin (Annexin)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .
Malate synthase, TIM barrel domain (Malate_synthase_TIM)
Type: Domain

This entry represents the TIM barrel domain of malate synthases.

Malate synthase (MS) (

) catalyses the aldol condensation of glyoxylate with acetyl-CoA to form malate as part of the second step of the glyoxylate bypass and an alternative to the tricarboxylic acid cycle in bacteria, fungi and plants. There have been identified two isoforms, A and G (MSA and MSG, respectively) that differ in size and is attributed to an inserted α/β domain in MSG that may have regulatory function . MSA and MSG consist of an N-terminal α-helical clasp domain, a central TIM-barrel domain and a C-terminal helical plug domain. In malate synthases, the TIM β/α-barrel fold and the C-terminal helical domain are well conserved and the cleft between them forms the active site .
Beta-lactamase-related (Beta-lactam-related)
Type: Domain

This entry represents the serine beta-lactamase-like superfamily. It is a group of diverse group of sequences that includes D-alanyl-D-alanine carboxypeptidase B, aminopeptidase (DmpB), alkaline D-peptidase, animal D-Ala-D-Ala carboxypeptidase homologues and the class A and C beta-lactamases and eukaryotic beta-lactamase homologues which are variously described as: transesterases, non-ribosomal peptide synthetases and hypothetical proteins. Many are serine peptidases belonging to MEROPS peptidase families S11 (D-Ala-D-Ala carboxypeptidase A family) and S12 (D-Ala-D-Ala carboxypeptidase B family, clan SE). The beta-lactamases are classified as both S11 and S12 non-peptidase homologues; these either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity.

Beta-lactamase catalyses the opening and hydrolysis of the beta-lactam ring of beta-lactam antibiotics such as penicillins and cephalosporins . There are four groups, classed A, B, C and D according to sequence, substrate specificity, and kinetic behaviour: class A (penicillinase-type) is the most common . The genes for class A beta-lactamases are widely distributed in bacteria, frequently located on transmissible plasmids in Gram-negative organisms, although an equivalent chromosomal gene has been found in a few species .

Class A, C and D beta-lactamases are serine-utilising hydrolases - class B enzymes utilise a catalytic zinc centre instead. The 3 classes of serine beta-lactamase are evolutionarily related and belong to a superfamily that also includes DD-peptidases and other penicillin-binding proteins . All these proteins contain an S-x-x-K motif, the Ser being the active site residue. Although clearly related, however, the sequences of the 3 classes of serine beta-lactamases vary considerably outside the active site.
Indole-3-glycerol phosphate synthase, conserved site (Indole-3-GlycerolPSynthase_CS)
Type: Conserved_site

Indole-3-glycerol phosphate synthase (

) (IGPS) catalyses the fourth step in the biosynthesis of tryptophan, the ring closure of 1-(2-carboxy-phenylamino)-1-deoxyribulose into indol-3-glycerol-phosphate. In some bacteria, IGPS is a single chain enzyme. In others, such as Escherichia coli, it is the N-terminal domain of a bifunctional enzyme that also catalyses N-(5'-phosphoribosyl)anthranilate isomerase (

) (PRAI) activity (see

), the third step of tryptophan biosynthesis. In fungi, IGPS is the central domain of a trifunctional enzyme that contains a PRAI C-terminal domain and a glutamine amidotransferase (

) (GATase) N-terminal domain.

A structure of the IGPS domain of the bifunctional enzyme from the mesophilic bacterium E. coli (eIGPS) has been compared with the monomeric indole-3-glycerol phosphate synthase from the hyperthermophilic archaeon Sulfolobus solfataricus (sIGPS). Both are single-domain (β/α)8 barrel proteins, with one (eIGPS) or two (sIGPS) additional helices inserted before the first β strand .

This entry represents a highly conserved region within the N-terminal section of IGPS, which has been shown to be part of the active site cavity.
ATP synthase, F1 complex, delta/epsilon subunit (ATP_synth_F1_dsu/esu)
Type: Family

This family represents subunits called delta (in mitochondrial ATPase) or epsilon (in bacteria or chloroplast ATPase). The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) . In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP,

) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity .

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.

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.
Bacteriochlorophyll c-binding protein (Bchl_c-bd)
Type: Family

Chlorosomes, which are attached to the inner surface of the cytoplasmic membrane, consist of four polypeptides and associated pigments and lipids. The principal light-harvesting pigment of the green filamentous bacterium Chloroflexus aurantiacus is bacteriochlorophyll (Bchl) c. This pigment is either bound to, or constrained by, a small approximately 80-residue polypeptide designated Bchlc-binding protein. In C. aurantiacus, a C-terminal extension is believed to play a role in proper incorporation of the protein during chlorosome assembly . The protein has a high degree of similarity to Bchlc-binding proteins of other photosynthetic bacteria.
AP2/ERF domain (AP2/ERF_dom)
Type: Domain

Ethylene is an endogenous plant hormone that influences many aspects of plant growth and development. Some defense related genes that are induced by ethylene contain a cis-regulatory element known as the Ethylene-Responsive Element (ERE) . Sequence analysis on various ERE regions has identified a short motif rich in G/C nucleotides, the GCC-box, essential for the response to ethylene. This short motif is recognised by a family of transcrition factors, the ERE binding factors (ERF) .

ERF proteins contain a domain of around 60 amino acids which is also found in the APETALA2 (AP2) protein . This AP2/ERF domain has been shown in various proteins to be necessary and sufficient to bind the GCC-box .

The structure of the AP2/ERF domain in complex with the target DNA has been solved . The structure resembles that of bacteriophage integrases and the methyl-CpG-binding domain (MBD): a three-stranded β-sheet and an α helix almost parallel to the β-sheet. It contacts DNA via Arg and Trp residues located in the β-sheet.
GTP cyclohydrolase I (GTP_CycHdrlase_I)
Type: Family

GTP cyclohydrolase I (

) catalyses the biosynthesis of formic acid and dihydroneopterin triphosphate from GTP . This reaction is the first step in the biosynthesis of tetrahydrofolate in prokaryotes, of tetrahydrobiopterin in vertebrates, and of pteridine-containing pigments in insects. The comparison of the sequence of the enzyme from bacterial and eukaryotic sources shows that the structure of this enzyme has been extremely well conserved throughout evolution .