SII-SWORD/CoKE huggingface dataset:
5-Hydroxytryptamine 1F receptor (5HT1F_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-HT1 receptors are a subfamily of 5-HT receptors that were originally classified according to their inhibition of adenylyl cyclase, degree of sequence similarity and their overlapping pharmacological specificities. The subfamily is comprised of five different receptors 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, and they can couple to Gi/Go and mediate inhibitory neurotransmission, although signalling via other transduction systems are known. One of the 5-HT1 receptors, the 5-HT1E receptor, is yet to achieve receptor status from the International Union of Basic and Clinical Pharmacology (IUPHAR), since a robust response mediated via the protein has not been reported in the literature.

This entry represents the 5-HT1F receptors, they are thought to be closely related 5-HT1E receptors. They have a limited distribution in peripheral tissues in human, and have been detected only in the uterus and mesentery . In the CNS, receptor mRNA is present in the cerebral cortex, hippocampus, raphe and spinal cord . Elucidation of the physiological role of 5-HT1F receptors requires development of selective ligands. At present, there are no selective antagonists or agonists. However, the 5-HT1D/5-HTD1B agonist and anti-migraine compound sumatriptan has reasonable affinity. Interestingly, 5-HT1F receptor expression has been detected in the trigeminal ganglia, stimulation of which leads to the plasma extravasation in the dura, a component of neurogenic inflammation thought to be a possible cause of migraine .
NF-kappa-B/Dorsal (NFkB/Dor)
Type: Family

The transcription factor NF-kB (Nuclear Factor-kappaB) was first identified as a DNA-binding protein specific for the 10-base pair kB site in the immunoglobulin k light-chain enhancer of B lymphocytes , but has subsequently been found in many different cell types. NF-kB represents a group of structurally related proteins that share a 300 amino acid `Rel homology domain' (RHD) : members include p50 (NF-kB1), p52 (NF-kB2), p65 (RelA), c-Rel, v-Rrel, RelB, and the Drosophila proteins Dorsal and Dif. These proteins exist as homo- and heterodimers that bind to kB sites in the enhancer regions of several target genes, most of which are involved in cellular defence mechanisms and differentiation.

The RHD, which is located N-terminally, is responsible for protein dimerisation, DNA binding and nuclear localisation. The more variable C-terminal transactivation domain is found in RelA, RelB and c-Rel, but not in p50 or p52. Nevertheless, p50 and p52 play critical roles in modulating the specificity of NF-kB function. DNA binding requires the entire RHD, by contrast with other eukaryotic and prokaryotic transcription factors, where much smaller DNA-binding domains confer full specificity and binding affinity for the target . The structure of the transcription factor NF-kB p50 homodimer bound to a palindromic kB site shows the RHD to fold into 2 distinct subdomains, similar to the β-sandwich structure of the immunoglobulins .

NF-kB is expressed in the cytoplasm of virtually all cell types, where its activity is controlled by a family of regulatory proteins, called inhibitors of NF-kB (IkB) .
Kappa opioid receptor (Kappa_opi_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 .

The term opioid refers to a class of substance that produces its effects via the major classes of opioid receptor, termed mu, delta and kappa. In the CNS, the kappa opioid receptor is found in the cerebral cortex, substantia nigra, interpeduncular nucleus, striatum and hippocampus. In the periphery, it is found in the myenteric plexus of the guinea pig ileum, and it is also in certain smooth muscles, e.g. rabbit vas deferens. K-opioid receptors are believed to mediate analgesia, sedation, miosis and diuresis. Dynorphin is the most potent endogenous ligand.
Chorismate synthase (Chorismate_synth)
Type: Family

Chorismate synthase (CS; 5-enolpyruvylshikimate-3-phosphate phospholyase; 1-carboxyvinyl-3-phosphoshikimate phosphate-lyase; E.C. 4.2.3.5) catalyzes the seventh and final step in the shikimate pathway which is used in prokaryotes, fungi and plants for the biosynthesis of aromatic amino acids. It catalyzes the 1,4-trans elimination of the phosphate group from 5-enolpyruvylshikimate-3-phosphate (EPSP) to form chorismate which can then be used in phenylalanine, tyrosine or tryptophan biosynthesis. Chorismate synthase requires the presence of a reduced flavin mononucleotide (FMNH2 or FADH2) for its activity. Chorismate synthase from various sources shows a high degree of sequence conservation . It is a protein of about 360 to 400 amino-acid residues.

Depending on the capacity of these enzymes to regenerate the reduced form of FMN, chorismate synthases are divided into two groups: enzymes, mostly from plants and eubacteria, that sequester CS from the cellular environment, are monofunctional, while those that can generate reduced FMN at the expense of NADPH, such as found in fungi and the ciliated protozoan Euglena gracilis, are bifunctional, having an additional NADPH:FMN oxidoreductase activity. Recently, bifunctionality of the Mycobacterium tuberculosis enzyme (MtCS) was determined by measurements of both chorismate synthase and NADH:FMN oxidoreductase activities. Since shikimate pathway enzymes are present in bacteria, fungi and apicomplexan parasites (such as Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum) but absent in mammals, they are potentially attractive targets for the development of new therapy against infectious diseases such as tuberculosis (TB) .
ATP synthase, F0 complex, subunit C (ATP_synth_F0_csu)
Type: Family

This entry represents subunit C (also called subunit 9, or proteolipid) found in the F0 complex of F-ATPases. Ten C subunits form an oligomeric ring that makes up the F0 rotor. The flux of protons through the ATPase channel drives the rotation of the C subunit ring, which in turn is coupled to the rotation of the F1 complex gamma subunit rotor due to the permanent binding between the gamma and epsilon subunits of F1 and the C subunit ring of F0. The sequential protonation and deprotonation of Asp61 of subunit C is coupled to the stepwise movement of the rotor .

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.
Large ribosomal subunit protein bL17 (Ribosomal_bL17)
Type: Family

This entry represents ribosomal subunit protein bL17 family from bacteria and eukaryotes.

Large ribosomal subunit protein bL17 (also known as L17) is one of the proteins from the large ribosomal subunit. Bacterial L17 is a protein of 120 to 130 amino-acid residues while yeast YmL8 is twice as large (238 residues). The N-terminal half of YmL8 is collinear with the sequence of L17 from Escherichia coli.

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 .
Mucin-like glycoprotein (Tryp_mucin)
Type: Family

This family of trypanosomal proteins resemble vertebrate mucins. The protein consists of three regions. The N and C terminii are conserved between all members of the family, whereas the central region is not well conserved and contains a large number of threonine residues which can be glycosylated . Indirect evidence suggested that these genes might encode the core protein of parasite mucins, glycoproteins that were proposed to be involved in the interaction with, and invasion of, mammalian host cells.
Neuroligin (Nlgn)
Type: Family

Neuroligins (NLGNs) interact with the neurexin family members and are involved in the modulation of synaptic transmission . Mammals have four Nlgn proteins, with the Nlgn3 and Nlgn4 gene in humans localised to the X-chromosome. In humans, the Nlgn4 gene is complemented on the Y-chromosome by a similar Nlgn5 gene .
CDP-alcohol phosphatidyltransferase (CDP-OH_P_trans)
Type: Family

A number of phosphatidyltransferases, which are all involved in phospholipid biosynthesis and that share the property of catalysing the displacement of CMP from a CDP-alcohol by a second alcohol with formation of a phosphodiester bond and concomitant breaking of a phosphoride anhydride bond share a conserved sequence region . These enzymes are proteins of 200 to 400 amino acid residues, including EPT1 from yeast, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferases from bacteria, CDP-diacylglycerol--serine O-phosphatidyltransferase from animals, among others. Also included in this entry is cardiolipin (CL) synthase (CMP-forming)/mitochondrial hydrolase fusion protein from S.pombe, a tandem fusion protein with a mitochondrial hydrolase. The CL synthase is essential for this organism .
Cytosolic fatty-acid binding (Fatty_acid-bd)
Type: Domain

The Fatty Acid-Binding Proteins (FABPs) are a family of proteins that are principally located in the cytosol and are characterised by the ability to bind to hydrophobic ligands, such as fatty acids, retinol, retinoic acid, bile salts and pigments . Recently, a number of family members have been identified that are secreted, such as gastrotropin and mammary-derived growth inhibitor. The family is implicated in general lipid metabolism, acting as intracellular transporters of hydrophobic metabolic intermediates and as carriers of lipids between membranes . The FABPs exhibit a high degree both of sequence and structural similarity. They are small, 12-18kDa, soluble proteins composed of 110-160 residues. Their crystal structures show them to be 10-stranded anti-parallel β-barrels with a +1,+1 topology, which wrap around an internal cavity to form a ligand binding site . Ligand specificity and affinity is governed by the side chains of amino acids that extend into the cavity, especially the polar residue that interacts through hydrogen bonding and electrostatic interactions with the polar head group of the ligand . An arginine or a glutamine residue is used for binding fatty acids or retinoids, respectively. The anti-parallel β-barrel fold is also exploited by the lipocalins, which function similarly by binding small hydrophobic molecules. Similarity at the sequence level, however, is less obvious, being confined to a single short N-terminal motif.
XPA/RAD14 (XPA/RAD14)
Type: Family

Xeroderma pigmentosum (XP) is a human autosomal recessive disease, characterised by a high incidence of sunlight-induced skin cancer. Skin cells of individual's with this condition are hypersensitive to ultraviolet light, due to defects in the incision step of DNA excision repair. There are a minimum of seven genetic complementation groups involved in this pathway: XP-A to XP-G. XP-A is the most severe form of the disease and is due to defects in a 30kDa nuclear protein called XPA (or XPAC) . The sequence of the XPA protein is conserved from higher eukaryotes to yeast (gene RAD14) . XPA is a hydrophilic protein of 247 to 296 amino-acid residues which has a C4-type zinc finger motif in its central section.
G-patch domain (G_patch_dom)
Type: Domain

The G-patch domain is an approximately 48 amino acid domain, which is found in a single copy in several RNA-associated proteins and in type D retroviral polyproteins. It is widespread among eukaryotes but is absent in archaea and bacteria. The G-patch domain has been called after its most notable feature, the presence of six highly conserved glycine residues. The position following the first conserved glycine is occupied almost invariably by an aromatic residue, and several other positions are occupied predominantly by either hydrophobic or small residues. Several groups of G-patch containing proteins are conserved in animals, plants and fungi. In some of these proteins the G- patch is the only recognisable domain but in most of them it is combined with other domains, which include well-defined RNA-binding domains, such as the RRM, dsRBD, SURP and R3H. It has been suggested that the G-patch domain has a specific function in RNA processing and, in particular, that it might be a previously undetected RNA-binding domain mediating a distinct type of RNA-protein interaction.

Secondary structure prediction indicates that the G-patch domain probably contains two α-helices, with four out of the six glycines located within an intervening loop.

Proteins known to contain a G-patch domain include:

Eukaryotic 45kDa splicing factor (SPF-45).

Mammmalian SON protein, a DNA-binding protein.

Human LUCA15, a multidomain RNA-binding protein that is the product of a gene deleted in certain lung tumors.

Human DAN26/EPROT, a multidomain protein, which, in addition to the G-patch domain, contains an RNA polymerase II C-terminal repeat-binding domain seen in many proteins of the polyA-addition machinery.

Arabidopsis thaliana DRT111, a protein which has been shown to partially restore recombination proficiency and DNA-damage resistance to E. coli mutants.

Type D retroviral polyprotein, where the G-patch domain is found directly downstream of the protease domain.
Barstar (barnase inhibitor) (Barstar)
Type: Domain

Barstar is a small single chain protein. Barnase is the extracellular ribonuclease

of Bacillus amyloliquefaciens, and barstar its specific intracellular inhibitor . Expression of barstar is necessary to counter the lethal effect of expressed active barnase.

The structure of the barstar consists of two layers of parallel β-sheet of three strands. Barstar inhibits barnase by statically blocking the active site with a helix and adjacent loop segment .
G-protein alpha subunit, group 12/13 (Gprotein_alpha_12/13)
Type: Family

Guanine nucleotide binding proteins (G-proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha (

), beta (

) and gamma (

) . G proteins and their receptors (GPCRs) form one of the most prevalent signalling systems in mammalian cells, regulating systems as diverse as sensory perception, cell growth and hormonal regulation . At the cell surface, the binding of ligands such as hormones and neurotransmitters to a GPCR activates the receptor by causing a conformational change, which in turn activates the bound G protein on the intracellular-side of the membrane. The activated receptor promotes the exchange of bound GDP for GTP on the G protein alpha subunit. GTP binding changes the conformation of switch regions within the alpha subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active alpha subunit (GTP-bound) and beta/gamma dimer. The alpha subunit and the beta/gamma dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, diacylglycerol, sodium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription. The cycle is completed by the hydrolysis of alpha subunit-bound GTP to GDP, resulting in the re-association of the alpha and beta/gamma subunits and their binding to the receptor, which terminates the signal . The length of the G protein signal is controlled by the duration of the GTP-bound alpha subunit, which can be regulated by RGS (regulator of G protein signalling) proteins or by covalent modifications .

G protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45kDa. Seventeen distinct types of alpha subunit have been identified in mammals. These fall into 4 main groups on the basis of both sequence similarity and function: alpha-S (

), alpha-Q (

), alpha-I (

)and alpha-12(

) .

The specific combination of subunits in heterotrimeric G proteins affects not only which receptor it can bind to, but also which downstream target is affected, providing the means to target specific physiological processes in response to specific external stimuli . G proteins carry lipid modifications on one or more of their subunits to target them to the plasma membrane and to contribute to protein interactions.

This family consists of the alpha-12 group of G proteins, which includes both alpha-12 group of G proteins and alpha-13 group of G proteins. G alpha-12 and G alpha-13 are ubiquitously expressed and can induce many cellular responses, including phospholipase C-epsilon activation, phospholipase D activation, cytoskeletal change, oncogenic response, apoptosis, MAP kinase activation and Na/H-exchange activation. G alpha-12 and G alpha-13 can activate several effectors, including small GTPases such as Rho .
CbxX/CfxQ, monofunctional (CbxX/CfqX_mono)
Type: Family

Proteins in this family are now designated CbbX. Some previously were CfxQ (carbon fixation Q). Its gene is often found immmediately downstream of the Rubisco large and small chain genes, and it is suggested to be necessary for Rubisco expression. CbbX has been shown to be necessary for photoautotrophic growth. The Cfx genes in Ralstonia eutropha (Alcaligenes eutrophus) encode a number of Calvin cycle enzymes . The observed sizes of two of the gene products, CfxX and CfxY,
are 35kDa and 27kDa respectively . No functions could be assigned to
CfxX and CfxY. These proteins show a high degree of similarity to the
Bacillus subtilis stage V sporulation protein K .
Activin types I and II receptor domain (Activin_recp)
Type: Domain

This is a hydrophilic cysteine-rich ligand-binding domain found in both TGF-beta receptor types (type I and II). In both types, this domain posses a 9 amino acid cysteine box, with the the consensus CCX{4-5}CN. The type I receptors also possess 7 extracellular residues preceding the cysteine box .

The Transforming growth factor-beta superfamily of ligands include: bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), anti-mullerian hormone (AMH), activin, nodal and TGF-beta. Signalling begins with the binding of a TGF-beta superfamily ligand to a TGF-beta type II receptors. The type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators .

The receptors for most of the members of this growth factor family are related. They are receptor-type kinases of Ser/Thr type, which have a single transmembrane domain and a specific hydrophilic Cys-rich ligand-binding domain .