SII-SWORD/CoKE huggingface dataset:
ATP phosphoribosyltransferase HisG (ATP_PRibTrfase_HisG)
Type: Family

ATP phosphoribosyltransferase (ATP-PRT,

) is the enzyme that catalyses the first step in the biosynthesis of histidine in bacteria, fungi and plants as shown below. It is a member of the larger phosphoribosyltransferase superfamily of enzymes which catalyse the condensation of 5-phospho-alpha-D-ribose 1-diphosphate with nitrogenous bases in the presence of divalent metal ions .

ATP + 5-phospho-alpha-D-ribose 1-diphosphate = 1-(5-phospho-D-ribosyl)-ATP + diphosphate

Histidine biosynthesis is an energetically expensive process and ATP-PRT activity is subject to control at several levels. Transcriptional regulation is based primarily on nutrient conditions and determines the amount of enzyme present in the cell, while feedback inhibition rapidly modulates activity in response to cellular conditions. The enzyme has been shown to be inhibited by 1-(5-phospho-D-ribosyl)-ATP, histidine, ppGpp (a signal associated with adverse environmental conditions) and ADP and AMP (which reflect the overall energy status of the cell). As this pathway of histidine biosynthesis is present only in prokaryotes, plants and fungi, this enzyme is a promising target for the development of novel antimicrobial compounds and herbicides.

ATP-PRT come in two forms: a long form containing two catalytic domains and a C-terminal regulatory domain, and a short form in which the regulatory domain is missing. The long form is catalytically competent, but in organisms with the short form, a histidyl-tRNA synthetase paralogue, HisZ, is required for enzyme activity .

The enzyme was initially thought to exist in equilibrium between an active dimeric form, an inactive hexameric form and higher aggregates . However, it has been shown later that this protein is a hexamer in equilibrium between an open and probably active state and a more compact closed and presumably inhibited form. These conformational changes are related to the allosteric inhibition by histidine. The ATP-PRT from Campylobacter jejuni is organised into three domains. The first two domains form a bilobal core unit that harbours the catalytic site in the cleft between them, where the binding of ATP and AMP is observed, and the C-terminal is a regulatory ACT domain, which binds histidine .
Cytochrome c oxidase, subunit VIa (Cyt_c_oxidase_su6a)
Type: Family

Cytochrome c oxidase (

) is an oligomeric enzymatic complex which is a component of the respiratory chain complex and is involved in the transfer of electrons from cytochrome c to oxygen . In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane.

In eukaryotes, in addition to the three large subunits, I, II and III, that form the catalytic centre of the enzyme complex, there are a variable number of small polypeptidic subunits. One of these subunits is known as VIa in vertebrates and fungi. Mammals have two tissue-specific isoforms of VIa, a liver (VIa-L) and a heart and skeletal muscle isoform (VIa-H). Mammalian VIa-H induces a slip in CcO (decrease in proton/electron stoichiometry) at high intramitochondrial ATP/ADP ratios, while VIa-L induces a permanent slip in CcO, depending on the presence of cardiolipin and palmitate . Only one form is found in fish .
G10D orphan receptor (G10D_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 .

Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. G10d was isolated from a rat genomic library and a liver cDNA library . It is widely distributed, being found in high levels in the lung, liver and adrenal gland, and also in the kidney, aorta, heart, spinal cord, gut and testis .
Small ribosomal subunit protein uS3, C-terminal (Ribosomal_uS3_C)
Type: Domain

This entry represents the C-terminal domain of the small ribosomal subunit protein uS3.

Small ribosomal subunit protein uS3 was previously known as Ribosomal protein S3. In Escherichia coli, S3 is known to be involved in the binding of initiator Met-tRNA. This family of ribosomal proteins includes S3 from bacteria, algae and plant chloroplast, cyanelle, archaebacteria, plant mitochondria, vertebrates, insects, Caenorhabditis elegans and yeast .

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 .
Ribonuclease HII/HIII (RNase_HII/HIII)
Type: Family

This family includes ribonuclease HII and HIII.

Ribonuclease H (RNase H) (

) is a member of the ribonuclease family, which recognises and cleaves the RNA strand of RNA-DNA heteroduplexes. The enzyme is widely present in all three kingdoms of living organisms, including bacteria, archaea, and eukaryotes, and their counterpart domains are also found in reverse transcriptases (RTs) from retroviruses and retroelements . RNases H are classified into two evolutionarily unrelated families, type-I and type-II RNase H, with common structural features of the catalytic domain but different range of substrates for enzymatic cleavage. There appears to be three evolutionarily distinct lineages of cellular Rnase H enzymes . Type-I or RNase HI domains have been found in all Eukarya, one Archaea, many Eubacteria, a few non-LTR retroposons and all LTR retrotransposons. Type II enzymes consist of RNase HII (rnhB) and HIII (rnhC), which are homologous enzymes. RNase HII can be found in Archaea, Eubacteria and all Eukarya, while RNase HIII appears only in some Eubacteria. In eukaryotes and all Archaea, RNase HII enzymes may constitute the bulk of all Rnase H activity, while the reverse is true in Eubacteria like E. coli where RNase HI is the major source of RNH activity . All LTR retrotransposons acquired an enzymatically weak RNase H domain that is missing an important catalytic residue found in all other RNase H enzymes. Vertebrate retroviruses appear to have reacquired their RNase H domains, which are catalytically more active, but their ancestral RNase H domains (found in other LTR retrotransposons) have degenerated to give rise to the tether domain unique to vertebrate retrovirus . Reverse transcriptase (RT) is a modular enzyme carrying polymerase and ribonuclease H (RNase H) activities in separable domains. Retroviral RNase H is synthesised as part of the POL polyprotein that contains an aspartyl protease, a reverse transcriptase, RNase H and integrase. POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins.
Proteasome, subunit alpha/beta (Proteasome_sua/b)
Type: Family

ATP-dependent protease complexes are present in all three kingdoms of life, where they rid the cell of misfolded or damaged proteins and control the level of certain regulatory proteins. They include the proteasome in Eukaryotes, Archaea, and Actinomycetales and the HslVU (ClpQY, clpXP) complex in other eubacteria. Genes homologues to eubacterial HslU (ClpY, clpX) have also been demonstrated in to be present in the genome of trypanosomatid protozoa .

The proteasome (or macropain) (

) is a multicatalytic proteinase complex in eukaryotes and archaea, and in some bacteria, that is involved in an ATP/ubiquitin-dependent non-lysosomal proteolytic pathway. In eukaryotes the 20S proteasome is composed of 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700kDa. Proteasome subunits can be classified on the basis of sequence similarities into two groups, alpha (A) and beta (B). The proteasome consists of four stacked rings composed of α/β/β/α subunits. There are seven different alpha subunits and seven different beta subunits . Three of the seven beta subunits are peptidases, each with a different specificity. Subunit beta1c (MEROPS identifier T01.010) has a preference for cleaving glutaminyl bonds ("peptidyl-glutamyl-like" or "caspase-like"), subunit beta2c (MEROPS identifier T01.011) has a preference for cleaving arginyl and lysyl bonds ("trypsin-like"), and subunit beta5c (MEROPS identifier T01.012) cleaves after hydrophobic amino acids ("chymotrypsin-like") . The proteasome subunits are related to N-terminal nucleophile hydrolases, and the catalytic subunits have an N-terminal threonine nucleophile.

The prokaryotic ATP-dependent proteasome is coded for by the heat-shock locus VU (HslVU). It consists of HslV, a peptidase, and HslU (

), the ATPase and chaperone belonging to the AAA/Clp/Hsp100 family. The crystal structure of Thermotoga maritima HslV has been determined to 2.1-A resolution. The structure of the dodecameric enzyme is well conserved compared to those from Escherichia coli and Haemophilus influenzae .

This entry contains threonine peptidases and non-peptidase homologues belong to MEROPS peptidase family T1 (proteasome family, clan PB(T)). The family consists of the protease components of the archaeal and bacterial proteasomes and the alpha and beta subunits of the eukaryotic proteasome.
CXC chemokine receptor 1 (Chemokine_CXCR1)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.

CXCR1 and CXCR2, also known as interleukin 8 receptor alpha and beta, respectively , are closely-related receptors. They act as specific receptors for the CXCL8 and CXCL6 chemokines, which have a glutamate-leucine-arginine (ELR) motif in their N-terminal domains . CXCR2 also binds additional ELR motif-containing CXC chemokines (such as
CXCL1, CXCL2, CXCL3, CXCL5 and CXCL7) with high affinity .

CXCR1 and CXCR2 are expressed on all granulocytes, monocytes, and mast cells and on some CD8+ T-cells and CD56+ natural killer (NK) cells . Equal amounts of CXCR1 and CXCR2 are present on neutrophils , but it appears that monocytes and positive lymphocytes express more CXCR2 than CXCR1 .

This entry represents CXCR1
Homeodomain (HD)
Type: Domain

This entry represents the homeodomain (HD), a protein domain of approximately 60 residues that usually binds DNA. It is encoded by the homeobox sequence , which was first identified in a number of Drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates , as well as plants , fungi and some species of lower eukaryotes. Many members of this group are transcriptional regulators, some of which operate differential genetic programs along the anterior-posterior axis of animal bodies . This domain folds into a globular structure with three α-helices connected by two short loops that harbour a hydrophobic core. The second and third form a helix-turn-helix (HTH) motif, which make intimate contacts with the DNA: while the first helix of this motif helps to stabilise the structure, the second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA. One particularity of the HTH motif in some of these proteins arises from the stereo-chemical requirement for glycine in the turn which is needed to avoid steric interference of the β-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, while for many of the homeotic and other DNA-binding proteins the requirement is relaxed.
BRCT domain (BRCT_dom)
Type: Domain

The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control . The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. BRCT domains are often found as tandem-repeat pairs . Some data indicate that the BRCT domain functions as a protein-protein interaction module.

The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography .

Structures of the BRCA1 BRCT domains revealed a basis for a widely utilised head-to-tail BRCT-BRCT oligomerization mode . This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants .
Neuropeptide Y2 receptor (NPY2_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 Y2 receptor. It is found in high levels in rat hippocampus , superficial layers of the cortex, certain thalamic nuclei, lateral septum, and anterior olfactory nuclei , lower levels are found in striatum. The receptors are also found in high levels in smooth muscle, such as vas deferens and intestine , kidney proximal tubules and in cell lines. Y2 receptors are believed to have a predominantly presynaptic location, and are involved in inhibition of adenylyl cyclase and voltage dependent calcium channels via a pertussis-toxin-sensitive G-protein, probably of the Gi protein class .
Synapsin (Synapsin)
Type: Family

The synapsins are a family of neuron-specific phosphoproteins that coat synaptic vesicles and are involved in the binding between these vesicles and the cytoskeleton (including actin filaments). The family comprises 5 homologous proteins Ia, Ib, IIa, IIb and III. Synapsins I, II, and III are encoded by 3 different genes. The a and b isoforms of synapsin I and II are splice variants of the primary transcripts .

Synapsin I is mainly associated with regulation of neurotransmitter release from presynaptic neuron terminals . Synapsin II, as well as being involved in neurotransmitter release, has a role in the synaptogenesis and synaptic plasticity responsible for long term potentiation . Recent studies implicate synapsin III with a developmental role in neurite elongation and synapse formation that is distinct from the functions of synapsins I and II .

Structurally, synapsins are multidomain proteins, of which 3 domains are common to all the mammalian forms. The N-terminal `A' domain is ~30 residues long and contains a serine residue that serves as an acceptor site for protein kinase-mediated phosphorylation. This is followed by the `B' linker domain, which is ~80 residues long and is relatively poorly conserved. Domain `C' is the longest, spanning approximately 300 residues. This domain is highly conserved across all the synapsins (including those from Drosophila) and is possessed by all splice variants. The remaining six domains, D-I, are not shared by all the synapsins and differ both between the primary transcripts and the splice variants.
Glycoside hydrolase family 1 (Glyco_hydro_1)
Type: Family

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.

Glycoside hydrolase family 1

comprises enzymes with a number of known activities; beta-glucosidase (

); beta-galactosidase (

); 6-phospho-beta-galactosidase (

); 6-phospho-beta-glucosidase (

); lactase-phlorizin hydrolase (

), (

); beta-mannosidase (

); myrosinase (

).
Gp90 envelope polyprotein of equine infectious anemia virus (EIAV) (Gp90_EIAV)
Type: Family

Equine infectious anemia virus(EIAV) belongs to the family retroviridae. EIAV gp90 is hypervariable in the carboxyl-end region and more stable in the amino-end region. This variability is a pathogenicity factor that allows the evasion of the host's immune response .
Glycoside hydrolase, family 32 (Glyco_hydro_32)
Type: Family

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.

Glycoside hydrolase family 32

comprises enzymes with several known activities; invertase/fructofuranosidase (

); inulinase (

); levanase (

); exo-inulinase (

); sucrose:sucrose 1-fructosyltransferase (

); fructan:fructan 1-fructosyltransferase (

).