SII-SWORD/CoKE huggingface dataset:
GPCR, family 3, metabotropic glutamate receptor 3 (GPCR_3_mGluR3)
Type: Family

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.

GRM3 is brain-specific, and is expressed in neurones in the cerebral cortex, caudate-putamen,
thalamus and cerebellum . GRM3 inhibits adenylyl cyclase through a
pertussis-toxin-sensitive G-protein, probably of the Gi/Go class. It has been related to neurological diseases such as amyotrophic lateral sclerosis and to cancer .
Lactate/malate dehydrogenase, N-terminal (Lactate/malate_DH_N)
Type: Domain

L-lactate dehydrogenases are metabolic enzymes which catalyse the conversion of
L-lactate to pyruvate, the last step in anaerobic glycolysis . L-lactate dehydrogenase is also found as a lens crystallin in bird and crocodile eyes. L-2-hydroxyisocaproate dehydrogenases are also members of the family. Malate dehydrogenases catalyse the interconversion of malate to oxaloacetate . The enzyme participates in the citric acid cycle.

This entry represents the N-terminal, and is thought to be a Rossmann NAD-binding fold.
43kDa postsynaptic protein (Postsynaptic)
Type: Family

The 43kDa postsynaptic protein is a peripheral membrane protein thought to be involved in the anchoring or stabilisation of the nicotinic acetylcholine receptor at synaptic sites . It may link the receptor to the postsynaptic cytoskeleton through direct association with actin or spectrin. The 43kDa protein is highly conserved across species. Two highly conserved regions, one encompassing the N terminus and the other near the C terminus, may be important for interaction of the protein with other components of the postsynaptic membrane.
DNA-binding, RecF (DNA-binding_RecF)
Type: Family

RecF belongs to the AAA+ superfamily of ATPases. All proteins in this family, including recF, are DNA binding proteins that assist the filamentation of RecA onto DNA for the initiation of recombination or recombinational repair. RecF is involved in DNA metabolism and is required for recombinational DNA repair and for induction of the SOS response .

The AAA+ superfamily of ATPases is found in all kingdoms of living organisms where they participate in diverse cellular processes including membrane fusion, proteolysis and DNA replication. Although the terms AAA+ and AAA are often used loosely and interchangeably, the classical AAA family members are distinguished by their possession of the SRH region in the AAA module. Many AAA+ proteins are involved in similar processes to those of AAA proteins (facilitation of protein folding and unfolding, assembly or disassembly of proteins complexes, protein transport and degradation), but others function in replication, recombination, repair and transcription. For a review see .
Proteinase inhibitor I1, Kazal-type, metazoa (Prot_inh_Kazal-m)
Type: Family

This family of Kazal eukaryotic proteinase inhibitors, belongs to MEROPS inhibitor family I1, clan IA. They inhibit serine peptidases of the S1 family (

) . They are restricted to the metazoa (arthropoda and chordata), and includes a single exception in the alveolata (apicomplexa). No members are found in nematodes, fungi or plants.

Kazal inhibitors, which inhibit a number of serine proteinases (such as trypsin and elastase), belong to family of proteins that includes pancreatic secretory trypsin inhibitor; avian ovomucoid; acrosin inhibitor; and elastase inhibitor. These proteins contain between 1 and 7 Kazal-type inhibitor repeats .

The structure of the Kazal repeat includes a large quantity of extended chain, 2 short α-helices and a 3-stranded anti-parallel β sheet .The inhibitor makes 11 contacts with its enzyme substrate: unusually, 8 of these important residues are hypervariable . Altering the enzyme-contact residues, and especially that of the active site bond, affects the the strength of inhibition and specificity of the inhibitor for particular serine proteinases .
N-(5'phosphoribosyl) anthranilate isomerase (PRAI) domain (PRAI_dom)
Type: Domain

N-(5'-phosphoribosyl) anthranilate isomerase (PRAI) is an enzyme that catalyses the third step of tryptophan biosynthesis. This domain can also be found at the C terminus of several multifunctional enzymes such as tryptophan biosynthesis protein TrpCF, TRP1 and TrpC.

Phosphoribosylanthranilate isomerase is monomeric and labile in most mesophilic microorganisms, but dimeric and stable in the hyperthermophile Thermotoga maritima (tPRAI) . The comparison to the known 2.0 A structure of PRAI from Escherichia coli (ePRAI) shows that tPRAI has the complete TIM- or (β α)8-barrel fold, whereas helix alpha5 in ePRAI is replaced by a loop. The subunits of tPRAI associate via the N-terminal faces of their central β-barrels. Two long, symmetry-related loops that protrude reciprocally into cavities of the other subunit provide for multiple hydrophobic interactions. Moreover, the side chains of the N-terminal methionines and the C-terminal leucines of both subunits are immobilized in a hydrophobic cluster, and the number of salt bridges is increased in tPRAI. These features appear to be mainly responsible for the high thermostability of tPRAI .
DNA topoisomerase, type IIA (Topo_IIA)
Type: Family

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

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

This entry represents DNA topoisomerase, type IIA.

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .

Type II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils .
Condensation domain (Condensation_dom)
Type: Domain

This domain is found in many multi-domain enzymes which synthesise peptide antibiotics. This domain catalyses a condensation reaction to form peptide bonds in non-ribosomal peptide biosynthesis. It is usually found on the carboxy side of a phosphopantetheine binding domain (pp-binding) (

). This domain was described as a pseudo-dimer of two lobes, the N-terminal lobe (N-lobe) and the C-terminal lobe (C-lobe), each of them consisting of one large central β-sheet, flanked by predominantly α-helices. The active site motif, HHxxxDG, is located in a loop that connects the central strand of the N-lobe and one of its long α-helices. Mutations in the HHXXXDG motif abolish the domain activity .
Rusticyanin (Rusticyanin)
Type: Family

Rusticyanin is a blue copper protein, described in an obligate acidophilic chemolithoautroph, Acidithiobacillus ferrooxidans, as an electron transfer protein. It can constitute up to 5 percent of protein in cells grown on Fe(II) and is thought to be part of an electron chain for Fe(II) oxidation, with two c-type cytochromes, an aa3-type cytochrome oxidase, and 02 as terminal electron acceptor . It is rather closely related to sulfocyanin (

).
Prostaglandin DP receptor (Prostglndn_DP_rcpt)
Type: Family

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 .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists.
Serine-threonine/tyrosine-protein kinase, catalytic domain (Ser-Thr/Tyr_kinase_cat_dom)
Type: Domain

This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include catalytic domain of dual specificity kinases.

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
Lipoxygenase, plant (LipOase_plant)
Type: Family

Lipoxygenases ([ec:1.13.11.-]) are a class of iron-containing dioxygenases which catalyses the hydroperoxidation of lipids, containing a cis,cis-1,4-pentadiene structure. They are common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding.

Lipoxygenases can be classified as 9- and 13-lipoxygenases, according to the position of oxygen incorporation in linoleic acid and linolenic acid, the most important substrates for LOX catalysis in plants. There are six A. thaliana lipoxygenases identified: AtLOX1-6, among which AtLOX-1 and AtLOX-5 are 9S-lipoxygenases, and AtLOX-2, AtLOX-3, AtLOX-4 and AtLOX-6 are 13S-lipoxygenases .
Exoribonuclease, phosphorolytic domain 1 (ExoRNase_PH_dom1)
Type: Domain

This entry represents the phosphorolytic (PH) domain 1, which has a core 2-layer α/β structure with a left-handed crossover, similar to that found in ribosomal protein S5. This domain is found in bacterial/organelle PNPases and in archaeal/eukaryotic exosomes .

The PH (phosphorolytic) domain is responsible for 3'-5' exoribonuclease activity, although in some proteins this domain has lost its catalytic function. An active PH domain uses inorganic phosphate as a nucleophile, adding it across the phosphodiester bond between the end two nucleotides in order to release ribonucleoside 5'-diphosphate (rNDP) from the 3' end of the RNA substrate.

PH domains can be found in bacterial/organelle RNases and PNPases (polynucleotide phosphorylases) , as well as in archaeal and eukaryotic RNA exosomes , the later acting as nano-compartments for the degradation or processing of RNA (including mRNA, rRNA, snRNA and snoRNA). Bacterial/organelle PNPases share a common barrel structure with RNA exosomes, consisting of a hexameric ring of PH domains that act as a degradation chamber, and an S1-domain/KH-domain containing cap that binds the RNA substrate (and sometimes accessory proteins) in order to regulate and restrict entry into the degradation chamber . Unstructured RNA substrates feed in through the pore made by the S1 domains, are degraded by the PH domain ring, and exit as nucleotides via the PH pore at the opposite end of the barrel .
Purine-cytosine permease (Pur-cyt_permease)
Type: Family

This entry represents the purine-cytosine permease family, whose members include allantoin permease Dal4 , nicotinamide riboside transporter 1 (Nrt1) , purine-cytosine permease Fcy2/21/22 , thiamine transporter Thi7/Thi72 , uracil permease Fur4 , uridine permease Fui1 and vitamin B6 transporter Tpn1 from budding yeasts. This entry also includes cytosine permeases codB from E. coli and purine-uracil permease AtNCS1 from Arabidopsis .
Acetyl-CoA biotin carboxyl carrier (AcCoA_biotinCC)
Type: Family

The proteins in this family are a component of the acetyl coenzyme A carboxylase complex (

) and are involved in the first step in long-chain fatty acid synthesis. In plants this is usually located in the chloroplast. In the first step, biotin carboxylase catalyses the carboxylation of the carrier protein to form an intermediate. Next, the transcarboxylase complex transfers the carboxyl group from the intermediate to acetyl-CoA forming malonyl-CoA. This protein functions in the transfer of CO
2
from one site to another, the biotin binding site locates to the C-terminal of this protein. The biotin is specifically attached to a lysine residue in the sequence AMKM.

The structure of the C-terminal domain of the biotin carboxyl carrier (BCC) protein was shown to be a flattened β-barrel structure comprising two four-stranded β sheets interrupted by a structural loop forming a thumb structure. The biotinyl-lysine is located on a tight β-turn on the opposite end of the molecule. The thumb structure has been shown to attached biotin, thus stabilising the structure.
Mannose-6-phosphate isomerase, type I (Man6P_Isoase-1)
Type: Family

Mannose-6-phosphate isomerase or phosphomannose isomerase (

) (PMI) is the enzyme that catalyses the interconversion of mannose-6-phosphate and fructose-6-phosphate. In eukaryotes PMI is involved in the synthesis of GDP-mannose, a constituent of N-and O-linked glycans and GPI anchors and in prokaryotes it participates in a variety of pathways, including capsular polysaccharide biosynthesis and D-mannose metabolism. PMI's belong to the cupin superfamily whose functions range from isomerase and epimerase activities involved in the modification of cell wall carbohydrates in bacteria and plants, to non-enzymatic storage proteins in plant seeds, and transcription factors linked to congenital baldness in mammals . Three classes of PMI have been defined .

Type I includes eukaryotic PMI and the enzyme encoded by the manA gene in enterobacteria. PMI has a bound zinc ion, which is essential for activity.

A crystal structure of PMI from
Candida albicans
shows that the enzyme has three distinct domains . The active site lies in the central domain, contains a single essential zinc atom, and forms a deep, open cavity of suitable dimensions to contain M6P or F6P The central domain is flanked by a helical domain on one side and a jelly-roll like domain on the other.
CRAL-TRIO lipid binding domain (CRAL-TRIO_dom)
Type: Domain

The CRAL-TRIO domain is a protein structural domain that binds small lipophilic molecules . The domain is named after cellular retinaldehyde-binding protein (CRALBP) and TRIO guanine exchange factor.

The CRAL-TRIO domain is found in GTPase-activating proteins (GAPs), guanine nucleotide exchange factors (GEFs) and a family of hydrophobic ligand binding proteins, including the yeast SEC14 protein and mammalian retinaldehyde- and alpha-tocopherol-binding proteins. The domain may either constitute all of the protein or only part of it .

The structure of the domain in SEC14 proteins has been determined . The structure contains several α helices as well as a β sheet composed of 6 strands. Strands 2,3,4 and 5 form a parallel β sheet with strands 1 and 6 being anti-parallel. The structure also identified a hydrophobic binding pocket for lipid binding.
Malate dehydrogenase, active site (Malate_DH_AS)
Type: Active_site

Malate dehydrogenase (

) (MDH) catalyzes the interconversion of malate to oxaloacetate utilizing the NAD/NADH cofactor system. The enzyme participates in the citric acid cycle and exists in all aerobics organisms.

While prokaryotic organisms contains a single form of MDH, in eukaryotic cells there are two isozymes: one which is located in the mitochondrial matrix and the other in the cytoplasm. Fungi and plants also harbor a glyoxysomal form which functions in the glyoxylate pathway. In plants chloroplast there is an additional NADP-dependent form of MDH (

) which is essential for both the universal C3 photosynthesis (Calvin) cycle and the more specialised C4 cycle.

The pattern for this enzyme includes two residues involved in the catalytic mechanism : an aspartic acid which is involved in a proton relay mechanism, and an arginine which binds the substrate.
Translation initiation factor 1A (eIF-1A) (TIF_eIF-1A)
Type: Family

Eukaryotic translation initiation factor A (eIF-1A) (formerly known as eiF-4C) is a protein that seems to be required for maximal rate of protein biosynthesis. It enhances ribosome dissociation into subunits and stabilises the binding of the initiator Met-tRNA to 40S ribosomal subunits . The archaea possess an eIF-1A homologue.