SII-SWORD/CoKE huggingface dataset:
Dopamine D2 receptor (Dopamine_D2_rcpt)
Type: Family

Dopamine receptors are members of the rhodopsin-like G-protein coupled receptor family and are prominent in the vertebrate central nervous system (CNS). Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders , including social phobia , Tourette's syndrome , Parkinson's disease , schizophrenia , neuroleptic malignant syndrome , attention-deficit hyperactivity disorder (ADHD) and drug and alcohol dependence . As a result, dopamine receptors are common drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors .

There are at least five different known subtypes of dopamine receptors designated D1, D2, D3, D4 and D5 . They are distinguished by their G-protein coupling, ligand specificity, anatomical distribution and physiological effects. Dopamine receptors are divided into two further subfamilies. The D1-like family consists of D1 and D5 receptors, which couple to Gs and mediate excitatory neurotransmission. The D2-like family, meanwhile, consists of D2, D3 and D4 receptors, which couple to Gi/Go and mediate inhibitory neurotransmission. Although dopamine receptors are widely distributed in the brain, they are found in different locations that have different receptor type densities, presumably reflecting different functional roles . D1 and D2 receptor subtypes are found at 10-100 times the levels of the D3, D4, D5 subtypes .

This entry represents the dopamine D2 receptors. They have a similar pharmacological profile to D3 and D4 receptors. The D2 receptor is present in high levels in the principal dopamine projection areas (including the caudate-putamen, nucleus accumbens and olfactory tubercle); they are found in cell bodies of dopaminergic neurons in the substantia nigra and ventral tegmental area, and in the periphery they are found in the pituitary, heart and blood vessels. In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood .

Dopamine D2 receptors have been shown to be important in the reward effects of morphine . D2 receptor knockout mice have been shown exhibit abnormal synaptic plasticity and to display reduced levels of aggression .
Prostanoid EP2 receptor (Prostglndn_EP2_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.

Prostaglandin E2 receptor EP2, also called prostanoid EP2 receptor, is one of four receptor subtypes whose endogenous physiological ligand is prostaglandin E2 (PGE2). Stimulation of the EP2 receptor by PGE2 causes cAMP accumulation through G(s) protein activation, which subsequently produces smooth muscle relaxation and mediates the systemic vasodepressor response to PGE2.
Porin, eukaryotic type (Porin_Euk)
Type: Family

Eukaryotic mitochondrial porins are voltage-dependent anion-selective channels (VDAC) that behave as general diffusion pores for small hydrophilic molecules . The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV.

The proteins are composed of between 12 to 16 β-strands that span the mitochondrial outer membrane. Yeast contains two members of this family (genes POR1 and POR2); vertebrates have at least three members (genes VDAC1, VDAC2 and VDAC3) . VDAC2 binds various lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterols cholesterol and oxysterol. Binding of ceramide promotes the mitochondrial outer membrane permeabilisation (MOMP) apoptotic pathway .
Tryptophan synthase beta chain-like, PALP domain (TrpB-like_PALP)
Type: Domain

This entry represents a domain found in a group of proteins of the PLP-dependent enzymes superfamily represented by the beta subunit of tryptophan synthase (TrpB) . This group of diverse proteins also include threonine dehydratase, cysteine synthase, threonine synthase and pyridoxal phosphate-dependent deaminase.
Sodium:galactoside symporter (Na/Gal_symport)
Type: Domain

It has been shown that integral membrane proteins that mediate the intake of a wide variety of molecules with the concomitant uptake of sodium ions (sodium symporters) can be grouped, on the basis of sequence and functional similarities into a number of distinct families. This collection of sequences represents the sodium: galactoside symporter family (SGF).

Like sugar transport proteins, these integral membrane proteins are predicted to comprise twelve membrane spanning domains.
Endothelin-like toxin (Endothln-like_toxin)
Type: Domain

Endothelins (ET's) are the most potent vasoconstrictors known . They stimulate cardiac contraction, regulate release of vasoactive substances, and stimulate mitogenesis in blood vessels in primary culture. They also stimulate contraction in almost all other smooth muscles (e.g., uterus, bronchus, vas deferensa and stomach) and stimulate secretion in several tissues (e.g., kidney, liver and adrenals). Endothelin receptors have also been found in the brain, e.g. cerebral cortex, cerebellum and glial cells. Endothelins have been implicated in a variety of pathophysiological conditions associated with stress, including hypertension, myocardial infarction, subarachnoid haemorrhage and renal failure.

Endothelins are synthesised by proteolysis of large preproendothelins, which are cleaved to 'big endothelins' before being processed to the mature peptide.

Sarafotoxins (SRTX) and bibrotoxin (BTX) are cardiotoxins from the venom of snakes of the Atractaspis family, structurally and functionally similar to endothelin.

As shown in the following schematic representation, these peptides which are 21 residues long contain two intramolecular disulphide bonds.

+-------------+
| |
CxCxxxxxxxCxxxCxxxxxx
| |
+-------+
'C': conserved cysteine involved in a disulphide bond.
Germin (Germin)
Type: Family

Germins (also known as Oxalate oxidases) and germin-like proteins are a family of hexameric ubiquitous plant glycoproteins. They are not restricted to germinating grains as initially sought and thereof called 'germins', but they exist in all organs and developmental stages. All are at least partly associated with the extracellular matrix.

A wide range of function has been uncovered for germins and germin-like proteins: some act as oxalate oxidases (

) or as superoxide dismutase (

), while others seem to be structural proteins or receptors for auxins or proteins. Germin catalyses the manganese-dependent oxidative decarboxylation of oxalate to carbon dioxide and hydrogen peroxide (H2O2) . It is widespread in fungi and various plant tissues and may play a role in plant signaling and defense.

Germins and germin-like proteins are highly similar to slime mold spherulins 1a and 1b which are proteins that accumulate specifically during spherulation, a process induced by various forms of environmental stress which leads to encystment and dormancy.
Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase (Peptidase_M1)
Type: Family

This group of metallopeptidases belong to the MEROPS peptidase family M1 (clan MA(E)), the type example being aminopeptidase N from Homo sapiens (Human). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.

Membrane alanine aminopeptidase (

) is part of the HEXXH
+
E group; it consists entirely of aminopeptidases, spread across a wide variety of species . Functional studies show that CD13/APN catalyses the removal of single amino acids from the amino terminus of small peptides and probably plays a role in their final digestion; one family member (leukotriene-A4 hydrolase) is known to hydrolyse the epoxide leukotriene-A4 to form an inflammatory mediator . This hydrolase has been shown to have aminopeptidase activity , and the zinc ligands of the M1 family were identified by site-directed mutagenesis on this enzyme CD13 participates in trimming peptides bound to MHC class II molecules and cleaves MIP-1 chemokine, which alters target cell specificity from basophils to eosinophils . CD13 acts as a receptor for specific strains of RNA viruses (coronaviruses) which cause a relatively large percentage of upper respiratory tract infections.
Small ribosomal subunit protein eS21 (Ribosomal_eS21)
Type: Family

This entry represents the small ribosomal subunit protein eS21 found in eukaryotes.

A number of eukaryotic ribosomal proteins can be grouped on the basis of sequence similarities. These proteins have 82 to 87 amino acids. The amino termini are all N alpha-acetylated. The N-terminal halves of the protein molecules are highly conserved in contrast to the carboxy-terminal parts .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
PPM-type phosphatase-like domain (PPM-type_phosphatase-like_dom)
Type: Domain

Protein phosphatases remove phosphate groups from various proteins that are the key components of a number of signalling pathways in eukaryotes and prokaryotes. Protein phosphatases that dephosphorylate Ser and Thr residues are classified into the phosphoprotein (PPP) and the protein phosphatase Mg2- or Mn2-dependent (PPM) families. The core structure of PPMs is the 300-residue PPM-type phosphatase domain that catalyses the dephosphorylation of phosphoserine- and phosphothreonine-containing protein. The PPM-type phosphatase domain is found as a module in diverse structural contexts and is modulated by targeting and regulatory subunits .

Some proteins known to contain a PPM-type phosphatase domain are listed below:

Bacillus subtilis stage II sporulation protein E (SpoIIE), controls the sporulation by dephosphorylating an anti-transcription factor SpoIIAA, reversing the actions of the SpoIIAB protein kinase in a process that is governed by the ADP/ATP ratio [levdikov].

Mycobacterium tuberculosis PP2C-family Ser/Thr phosphatase (PstP).

Eucaryotic PP2C, a negative regulator of protein kinase cascades that are activated as a result of stress.

Yeast adenylyl cyclase, plays essential roles in regulation of cellular metabolism by catalysing the synthesis of a second messenger, cAMP .

Mammalian mitochondrial pyruvate dehydrogenase phosphatase 1 (PDP1).

Plant kinase-associated protein phosphatase (KAPP), regulates receptor-like kinase (RLK) signalling pathways.

Plant absissic acid-insenstive 1 and 2 (ABI1 and ABI2), play a key absissic acid (ABA) signal transduction.

The PP2C-type phosphatase domain consists of 10 segments of β-strands and 5 segments of α-helix and comprises a pair of detached subdomains. The first is a small β-sandwich with strand β1 packed against strands β2 and β3; the second is a larger β-sandwich in which a four-stranded β-sheet packs against a three-stranded β-sheet with flanking α-helices .
Neuropeptide Y4 receptor (NPY4_rcpt)
Type: Family

Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat , facilitation of learning and memory via the modulation of hippocampal activity , inhibition of anxiety , presynaptic inhibition of neurotransmitter release in the CNS and periphery , and modulation of circadian rhythm . In the periphery, NPY stimulates vascular smooth muscle contraction , modulates the release of pituitary hormones , pain transmission , inhibition of insulin release and modulation of renal function . NPY has also been implicated in the pathophysiology of hypertension , congestive heart failure and appetite regulation and controlling epileptic seizures . Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue . These include inhibition of Ca2+ channels, such as in neurones , and activation and inhibition of K+ channels, such as in cardiomyocytes and vascular smooth muscle cells .

The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide . There are five pharmacologically distinct neuropeptide Y receptor subtypes ; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6).

This entry represents the neuropeptide Y4 receptor, it shows the highest similarity to Y1 receptors from human, rat and mouse . Y4 receptor is thought to have a potential role in central nervous system, cardiovascular and gastrointestinal function .
Ras GTPase-activating domain (RasGAP_dom)
Type: Domain

This entry represents a conserved domain in the RasGAPs (Ras GTPase-activating proteins). This domain is also known as the RasGAP domain.

Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP . This intrinsic GTPase activity of Ras is regulated by a family of proteins collectively known as 'GAP' or GTPase-activating proteins . RasGAP proteins are usually quite large (from 765 residues for sar1 to 3079 residues for IRA2) but share only a limited (about 250 residues) region of sequence similarity, referred to as the 'catalytic domain' or RasGAP domain. The most conserved region within this domain contains a 15 residue motif which seems to be characteristic of this family of proteins .
Galactose-1-phosphate uridyl transferase, class I (GalP_UDPtransf1)
Type: Family

Galactose-1-phosphate uridyl transferase

(GalT) catalyses the transfer of an uridyldiphosphate group on galactose (or glucose) 1-phosphate. During the reaction, the uridyl moiety links to a histidine residue. In the Escherichia coli enzyme, it has been shown that two histidine residues separated by a single proline residue are essential for enzyme activity.

On the basis of sequence similarities, two apparently unrelated families seem to exist. Class-I enzymes are found in eukaryotes as well as some bacteria such as E. coli or Streptomyces lividans, while class-II enzymes have been found so far only in bacteria such as Bacillus subtilis or Lactobacillus helveticus .
Thaumatin family (Thaumatin)
Type: Family

Thaumatin is an intensely sweet-tasting protein, 100 000 times sweeter than sucrose on a molar basis , found in berries from Thaumatococcus daniellii, a tropical flowering plant known as Katemfe. It is induced by attack by viroids, which are single-stranded unencapsulated RNA molecules that do not code for protein.

Thaumatin consists of about 200 residues and contains 8 disulphide bonds. Like other PR proteins, thaumatin is predicted to have a mainly β structure, with a high content of β-turns and little helix . Several stress-induced proteins of plants have been found to be related to thaumatins:

A maize alpha-amylase/trypsin inhibitor

Two tobacco pathogenesis-related proteins: PR-R major and minor forms, which are induced after infection with viruses

Salt-induced protein NP24 from tomato

Osmotin, a salt-induced protein from tobacco

Osmotin-like proteins OSML13, OSML15 and OSML81 from potato

P21, a leaf protein from soybean

PWIR2, a leaf protein from wheat

Zeamatin, a maize antifungal protein

This family is also referred to as pathogenesis-related group 5 (PR5), as many thaumatin-like proteins accumulate in plants in response to infection by a pathogen and possess antifungal activity . The proteins are involved in systemically acquired resistance and stress response in plants, although their precise role is unknown . The PR5K receptor protein kinase from Arabidopsis comprises an extracellular domain related to the PR5 proteins, and an intracellular protein-serine/threonine kinase domain .
Peptidase S1C (Peptidase_S1C)
Type: Family

This group of serine peptidases and non-peptidase homologues belong to the MEROPS peptidase family S1, subfamily S1C (protease Do subfamily, clan PS(S)). A type example is the protease Do from Escherichia coli.

This entry also includes the membrane transporter protein MamO and the magnetosome formation protease MamE. MamO promotes magnetite nucleation/formation and activates the MamE protease . MamE is required for correct localization of proteins to the magnetosome while the protease activity is required for maturation of small magnetite crystals into larger, functional ones .
Pro-opiomelanocortin (PMOC)
Type: Family

Pro-opiomelanocortin is present in high levels in the pituitary and is processed into 3 major peptide families: adrenocorticotrophin (ACTH); alpha-, beta- and gamma-melanocyte- stimulating hormones (MSH); and beta-endorphin . ACTH regulates the synthesis and release of glucocorticoids and, to some extent, aldosterone in the adrenal cortex. It is synthesised and released in response to corticotrophin-releasing factor at times of stress (i.e. heat, cold, infection, etc.), its release leading to increased metabolism. The action of MSH in man is poorly understood, but it may be involved in temperature regulation . Full activity of ACTH resides in the first 20 N-terminal amino acids, the first 13 of which are identical to alpha-MSH .
UVR domain (UVR_dom)
Type: Domain

During the process of Escherichia coli nucleotide excision repair, DNA damage recognition and processing are achieved by the action of the uvrA, uvrB, and uvrC gene products . UvrB and UvrC share a common domain of around 35 amino acids, the so called UVR domain. This domain in UvrB can interact with the homologous domain in UvrC throughout a putative coiled coil structure. This interaction is important for the incision of the damaged strand .

A conserved region similar to the UVR domain is also found in the ATP-binding subunit of bacterial and chloroplastic Clp ATPases , which suggest that the UVR domain is not only involved in the interaction between uvrB and uvrC.
Glycoside hydrolase, family 35 (Glycoside_Hdrlase_35)
Type: Family

Glycoside hydrolase family 35 (

) comprises enzymes with only one known activity: beta-galactosidase (

). Mammalian beta-galactosidase is a lysosomal enzyme (gene GLB1 ) that cleaves the terminal galactose from gangliosides, glycoproteins, and glycosaminoglycans and whose deficiency is the cause of the genetic disease Gm(1) gangliosidosis (Morquio disease type B). Beta-1,2-glucosyltransferase from gnavibacterium album [

] is classified as part of the GH35 family (

). This enzyme transfers a glucosyl residue from the non-reducing end of a 1,2-beta-D-glucan to a glucose residue of an acceptor molecule, forming a beta(1,2) linkage .

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.