SII-SWORD/CoKE huggingface dataset:
Prostaglandin D receptor (Pglndn_D_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.

DP receptors have a limited distribution. They mediate relaxation in vascular, gastrointestinal and uterine smooth muscle in human and some other species; they inhibit platelet activation, and modify release of hypothalamic and pituitary hormones. The receptors activate adenylyl cyclase through G proteins.
5-Hydroxytryptamine 2C receptor (5HT2C_rcpt)
Type: Family

5-hydroxytryptamine (5-HT) or serotonin, is a neurotransmitter that it is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS). It is implicated in a vast array of physiological and pathophysiological pathways. Receptors for 5-HT mediate both excitatory and inhibitory neurotransmission, and modulate the release of many neurotransmitters including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin and cortisol. In the CNS, 5-HT receptors can influence various neurological processes, such as aggression, anxiety and appetite and, as a, result are the target of a variety of pharmaceutical drugs, including many antidepressants, antipsychotics and anorectics .

The 5-HT receptors are grouped into a number of distinct subtypes, classified according to their antagonist susceptibilities and their affinities for 5-HT. With the exception of the 5-HT3 receptor, which is a ligand-gated ion channel , all 5-HT receptors are members of the rhodopsin-like G protein-coupled receptor family , and they activate an intracellular second messenger cascade to produce their responses.

The 5-HT2 receptors mediate many of the central and peripheral physiologic functions of 5-hydroxytryptamine. The original 5HT2 receptor (now renamed as the 5-HT2A receptor) was initially classified according to its ability to display micromolar affinity for 5-HT, to be labelled with [3H]spiperone and by its susceptibility to 5-HT antagonists. At least 3 members of the 5HT2 receptor subfamily exist (5-HT2A, 5-HT2B, 5-HT2C), all of which share a high degree of sequence similarity and couple to Gq/G11 to stimulate the phosphoinositide pathway and elevate cytosolic calcium. Cardiovascular effects include contraction of blood vessels and shape changes in platelets; central nervous system effects include neuronal sensitisation to tactile stimuli and mediation of some of the effects of phenylisopropylamine hallucinogens. 5-HT2 receptors display functional selectivity in which the same agonist in different cell types or different agonists in the same cell type can differentially activate multiple, distinct signalling pathways .

The distribution of 5-HT2C is limited to the CNS and choroid plexus . Activation of the receptor has been shown to exert an inhibitory influence upon frontocortical dopaminergic and adrenergic, but not serotonergic transmission and, in part, to play a role in neuroendocrine function . Additional characteristic behavioural responses attributed to 5-HT2C receptor activation include hypoactivity , feeding , reproductive behaviour and thermoregulation . Chronic treatment with antipsychotic drugs that are 5-HT2 antagonists results in downregulation of both 5-HT2A and 5-HT2C receptors, as does chronic treatment with SSRIs and 5-HT agonists . However, chronic SSRI treatment may increase 5-HT2C expression, specifically in the choroid plexus .
Opsin red/green sensitive (Opsin_red/grn)
Type: Family

Opsins are the photoreceptors of animal retinas . Vertebrate rhodopsin is found in rod cells and mediates scotopic vision; red, green and blue opsins are found in cone cells and mediate photopic vision. Red-sensitive opsin has an absorption maximum at 560nm; its deficiency results in protanopia colour blindness . Green-sensitive opsin has an absorption maximum at 530nm; its deficiency results in deuteranopia colour blindness . The ratio of green and red cones to rods is ~1:30.
DNA topoisomerase, type IA (Topo_IA)
Type: Family

This entry describes the type IA topoisomerases, which are highly conserved enzymes that are structurally distinct from type IB enzymes. The structures of both topoisomerases I and III have been elucidated, and consist of four domains that together form a toroidal molecule with a central hole that is large enough to accommodate single- and double-stranded DNA . It is believed that the domains transiently separate from one another to allow the entrance and exit of DNA strands.

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

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

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

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .
Inhibin, beta B subunit, C-terminal (INHBB_C)
Type: Domain

Inhibins and activins are glycoproteins, secreted by the gonads, that belong to the transforming growth factor beta family . They participate in differentiation and growth of diverse cell types. Inhibin inhibits secretion of follicle-stimulating hormone by the pituitary .

Inhibin has two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits.

Activin A is a dimer of beta A subunits, activin AB is a dimer of beta A and beta B chains.

This entry represents the C-terminal domain of INHBB.
Peptidase S39B, luteovirus (Peptidase_S39B_luteovirus)
Type: Domain

ORF2 of Potato leafroll virus (PLrV) encodes a polyprotein which is translated following a -1 frameshift. The polyprotein has a putative linear arrangement of membrane achor-VPg-peptidase-polmerase domains. The serine peptidase domain which is found in this group of sequences belongs to MEROPS peptidase family S39 (clan PA(S)). It is likely that the peptidase domain is involved in the cleavage of the polyprotein .

The nucleotide sequence for the RNA of PLrV has been determined . The sequence contains six large open reading frames (ORFs). The 5' coding region encodes two polypeptides of 28K and 70K, which overlap in different reading frames; it is suggested that the third ORF in the 5' block is translated by frameshift readthrough near the end of the 70K protein, yielding a 118K polypeptide . Segments of the predicted amino acid sequences of these ORFs resemble those of known viral RNA polymerases, ATP-binding proteins and viral genome-linked proteins. The nucleotide sequence of the genomic RNA of Beet western yellows virus (BWYV) has been determined . The sequence contains six long ORFs. A cluster of three of these ORFs, including the coat protein cistron, display extensive amino acid sequence similarity to corresponding ORFs of a second luteovirus: Barley yellow dwarf virus .
Xaa-Pro dipeptidyl-peptidase-like domain (Xaa-Pro-like_dom)
Type: Domain

This entry represents a domain found in Xaa-Pro dipeptidyl-peptidases, which belong to MEROPS peptidase family S15 . It is also found in hydrolases from the CocE/NonD family. Cocaine esterase (CocE) hydrolyses cocaine endowing the bacteria with the ability to utilise cocaine as a sole source of carbon and energy .
MoaA/NifB/PqqE, iron-sulphur binding, conserved site (MoaA_NifB_PqqE_Fe-S-bd_CS)
Type: Conserved_site

A number of proteins involved in the biosynthesis of metallo cofactors have been shown to be evolutionary related. These include:

Bacterial and archebacterial protein moaA, which is involved in the biosynthesis of the molybdenum cofactor (molybdopterin; MPT).

Arabidopsis thaliana (Mouse-ear cress) cnx2, a protein involved in molybdopterin biosynthesis and which is highly similar to moaA.

Bacillus subtilis narA, which seems to be the moaA ortholog in that bacteria.

Bacterial protein nifB (or fixZ) which is involved in the biosynthesis of the nitrogenase iron-molybdenum cofactor.

Bacterial protein pqqE which is involved in the biosynthesis of the cofactor pyrrolo-quinoline-quinone (PQQ).

Pyrococcus furiosus cmo, a protein involved in the synthesis of a molybdopterin-based tungsten cofactor.

Caenorhabditis elegans hypothetical protein F49E2.1.

These proteins share, in their N-terminal region, a conserved domain that contains three cysteines. In moaA, these cysteines have been shown to be important for biological activity by binding a [4Fe-4S] cluster . The three cysteines each coordinate one Fe, while S-adenosylmethionine is the fourth ligand to the cluster and binds to its unique Fe as an N/O chelate.
Haemagglutinin, influenzavirus B (Hemagglutn_influenz_B)
Type: Family

Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics . The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.

The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets . Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two α helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.

This entry represents haemagglutinin found in influenza virus B.
Tyrosine-specific protein phosphatases domain (Tyr_Pase_dom)
Type: Domain

Tyrosine specific protein phosphatases (PTPases) contain two conserved cysteines, the second one has been shown to be absolutely required for activity. This entry represents the PTPase domain that centre on the active site cysteine. A number of conserved residues in its immediate vicinity have also been shown to be important.

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

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

(1) pTyr-specific phosphatases

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

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

(4) LMW (low molecular weight) phosphatases

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

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

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.
ATP-binding cassette sub-family C member 8/9 (ABCC8/9)
Type: Family

This entry represents the ATP-binding cassette sub-family C member 8 and 9 (ABCC8/9, also known as sulfonylurea receptors SUR1/2), a subunit of the beta cell potassium channel (KATP) that associates with certain K
+
channel inward rectifier subunits to form ATP-sensitive K
+
channels (KATP channels) . These are a family of K
+
channels that are inhibited by intracellular ATP, which can couple metabolic state to cell excitability. Their presence on pancreatic islet beta cells allows the cells to function as metabolic sensors, regulating insulin release in relation to glucose metabolism. Furthermore, SUR is the site of action for the sulfonylurea oral hypoglycemic agents that are used widely for the treatment of non-insulin dependent diabetes mellitus. When these agents bind to the sulfonylurea receptor, they reduce KATP channel activity, stimulating insulin release.

SUR1/2 are ABC transporter-like proteins that belong to the ABC transporter family. These proteins are encoded by two closely related genes, of which the second form has three splice variants . They contain 13-17 transmembrane (TM) domains, with two adenosine nucleotide binding sites nestled in between two nucleotide binding domains (NBDs) . SUR1 has been described as an ADP sensor .

Mutations in SUR genes have been characterised; these can result in truncations of the second predicted nucleotide binding fold, leading to persistent hyperinsulinemic hypoglycemia of infancy, a rare familial disorder characterised by excessive, unregulated insulin secretion.
Small hydrophilic plant seed protein (Small_hydrophilic_seed_prot)
Type: Family

This entry contains the plant LEA (late embryogenesis abundant) proteins, which are small hydrophilic plant seed proteins that are structurally related. These proteins contains from 83 to 153 amino acid residues and may play a role in equipping the seed for survival, maintaining a minimal level of hydration in the dry organism and preventing the denaturation of cytoplasmic components. They may also play a role during imbibition by controlling water uptake.
Small drug/metabolite transporter protein family (Small_drug/metabolite_transptr)
Type: Family

Members of this family which have been characterised, belong to the small multidrug/metabolite transporter family and are integral membrane proteins. They confer resistance to a wide range of toxic compounds by removing them for the cells. The efflux is coupled to an influx of protons. It includes 4-amino-4-deoxy-L-arabinose-phosphoundecaprenol flippase subunit ArnE and ArnF, which are components of the undecaprenyl-phosphate-alpha-L-Ara4N flippase that translocates 4-amino-4-deoxy-L-arabinose-phosphoundecaprenol from the cytoplasmic to the periplasmic side of the inner membrane during lipopolysaccharide biosynthesis and is involved in polymyxin resistance . Another example is Escherichia coli EmrE

which confers resistance to a wide range of toxic compounds, including ethidium, methyl viologen , benzalkonium, propidium, dequalinium and different aromatic cation antibiotics and it is also involved in ethidium bromide efflux . It simultaneously binds and cotransports proton and drug .
Ring-hydroxylating dioxygenase beta subunit (Rng_hydr_dOase-bsu)
Type: Family

This entry represents the ring hydroxylating dioxygenase beta subunit. This subunit has a similar structure to NTF-2, Ketosteroid isomerase and scytalone dehydratase. The degradation of aromatic compounds by aerobic bacteria frequently begins with the dihydroxylation of the substrate by nonhaem iron-containing dioxygenases. These enzymes consist of two or three soluble proteins that interact to form an electron-transport chain that transfers electrons from reduced nucleotides (NADH) via flavin and [2Fe-2S] redox centres to a terminal dioxygenase . Aromatic-ring-hydroxylating dioxygenases oxidise aromatic hydrocarbons and related compounds to cis-arene diols. These enzymes utilise a mononuclear non-haem iron centre to catalyse the addition of dioxygen to their respective substrates. The active site of these enzymes however is in the alpha subunit. No functional role has been attributed to the beta subunit except for a structural role .
NifH/frxC family (NifH/frxC)
Type: Family

This entry includes the bacterial nitrogenase iron protein NifH , chloroplast encoded chlL (or frxC) , and archaeal Ni-sirohydrochlorin a,c-diamide reductive cyclase complex component CfbC .

Nitrogenase (

) is responsible for biological nitrogen fixation. Nitrogenase is an oligomeric complex which consists of two components: component 1 which contains the active site for the reduction of nitrogen to ammonia and component 2 (also called the iron protein) . Component 2 is a homodimer of a protein (gene nifH) which binds a single 4Fe-4S iron sulfur cluster. In the nitrogen fixation process NifH is first reduced by a protein such as ferredoxin; the reduced protein then transfers electrons to component 1 with the concomitant consumption of ATP .

There are a number of conserved regions in the sequence of these proteins: in the N-terminal section there is an ATP-binding site motif 'A' (P-loop) and in the central section there are two conserved cysteines which have been shown, in NifH, to be the ligands of the 4Fe-4S cluster.

Protochlorophyllide reductase is involved in light-independent chlorophyll biosynthesis. The light-independent reaction uses Mg-ATP and reduced ferredoxin to reduce ring D of protochlorophyllide (Pchlide) to form chlorophyllide a (Chlide). This enzyme complex is composed of three subunits: ChlL, ChlN and ChlB. ChlL (also known as frxC) is present as a homodimer, and binds one 4Fe-4S cluster per dimer. The conserved domains, including the ATP-binding motif and the Fe-S binding motif found in the three subunits, are similar to those in nitrogenases .