SII-SWORD/CoKE huggingface dataset:
Glutathione S-transferase, C-terminal (GST_C)
Type: Domain

In eukaryotes, glutathione S-transferases (GSTs) participate in the detoxification of reactive electrophilic compounds by catalysing their
conjugation to glutathione. The GST domain is also found in S-crystallins from squid, and proteins with no known GST activity, such as eukaryotic elongation factors 1-gamma and the HSP26 family of stress-related proteins, which include auxin-regulated proteins in plants and stringent starvation proteins in Escherichia coli. The major lens polypeptide of cephalopods is also a GST .

Bacterial GSTs of known function often have a specific, growth-supporting role in biodegradative metabolism: epoxide ring opening and tetrachlorohydroquinone reductive dehalogenation are two examples of the reactions catalysed by these bacterial GSTs. Some regulatory proteins, like the stringent starvation proteins, also belong to the GST family . GST seems to be absent from Archaea in which gamma-glutamylcysteine substitute to glutathione as major thiol.

Glutathione S-transferases form homodimers, but in eukaryotes can also form heterodimers of the A1 and A2 or YC1 and YC2 subunits. The homodimeric enzymes display a conserved structural fold. Each monomer is composed of a distinct N-terminal sub-domain, which adopts the thioredoxin fold, and a C-terminal all-helical sub-domain. This entry is the C-terminal domain.
Epsilon tubulin (Epsilon_tubulin)
Type: Family

Microtubules are polymers of tubulin, a dimer of two 55kDa subunits, designated alpha and beta . Within the microtubule lattice, α-β heterodimers associate in a head-to-tail fashion, giving rise to microtubule polarity. Fluorescent labelling studies have suggested that tubulin is oriented in microtubules with beta-tubulin toward the plus end .

For maximal rate and extent of polymerisation into microtubules, tubulin requires GTP. Two molecules of GTP are bound at different sites, termed N and E. At the E (Exchangeable) site, GTP is hydrolysed during incorporation into the microtubule. Close to the E site is an invariant region rich in glycine residues, which is found in both chains and is thought to control access of the nucleotide to its binding site .

Most species, excepting simple eukaryotes, express a variety of closely-related alpha- and beta-isotypes. A third family member, gamma tubulin, has also been identified in a number of species. Gamma tubulin is found at microtubule-organising centres, such as the spindle poles or the centrosome, suggesting that it is involved in minus-end nucleation of microtubule assembly . More recently, epsilon-tubulin has been identified in humans and Trypanosomes . In Tetrahymena is required for the assembly and maintenance of the triplet microtubule blades of basal bodies. In humans, it has been localised to centrosomes . It is required for centriole duplication and organisation of the pericentriolar material .
Zeta tubulin (Zeta_tubulin)
Type: Family

Microtubules are polymers of tubulin, a dimer of two 55kDa subunits, designated alpha and beta . Within the microtubule lattice, α-β heterodimers associate in a head-to-tail fashion, giving rise to microtubule polarity. Fluorescent labelling studies have suggested that tubulin is oriented in microtubules with beta-tubulin toward the plus end .

For maximal rate and extent of polymerisation into microtubules, tubulin requires GTP. Two molecules of GTP are bound at different sites, termed N
and E. At the E (Exchangeable) site, GTP is hydrolysed during incorporation into the microtubule. Close to the E site is an invariant region rich in glycine residues, which is found in both chains and is thought to control access of the nucleotide to its binding site .

Most species, excepting simple eukaryotes, express a variety of closely-related alpha- and beta-isotypes. A third family member, gamma tubulin, has also been identified in a number of species. Gamma tubulin is found at microtubule-organising centres, such as the spindle poles or the centrosome, suggesting that it is involved in minus-end nucleation of microtubule assembly . More recently, zeta-tubulin has been identified in Trypanosoma brucei and Leishmania major , and a partial sequence has also been identified in Xenopus laevis .

Zeta-tubulin is largely uncharacterised and, together with epsilon- and delta-tubulin, forms an evolutionarily co-conserved module, named the ZED module, that has been lost at several junctions in eukaryotic evolution and it has been shown that zeta- and delta-tubulin are evolutionarily interchangeable . The localization and function of zeta-, epsilon- and delta-tubulins is unknown in trypanosomatids.
Orexin/Hypocretin receptor type 1 (OX1R)
Type: Family

The neuropeptide hormone orexin stimulates appetite and food consumption , and is found in the hypothalamus, which has been shown to be the 'feeding centre' and plays a central role in the integrated control of feeding and energy homeostasis . It also has a prominent role in promoting wakefulness . The orexin receptor (also referred to as the hypocretin receptor) is a rhodopsin-like G protein-coupled receptor that binds orexin. There are two subtypes; orexin receptor 1 (OX1) and orexin receptor 2 (OX2) .

This entry represents Orexin/Hypocretin receptor type 1 (OX1R), which is found many in mammalian tissues and mostly expressed in the hypothalamus. This protein has a moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide . In response to orexin-A binding, it triggers an increase in cytoplasmic Ca2+ levels . OX1 receptor signaling in sleep/wake regulation is not as well defined as for the OX2 receptor, but it has been implicated in feeding, water intake, spatial learning and reward pathways .
Orexin receptor 2 (Orexin_rcpt_2)
Type: Family

The neuropeptide hormone orexin stimulates appetite and food consumption , and is found in the hypothalamus, which has been shown to be the 'feeding centre' and plays a central role in the integrated control of feeding and energy homeostasis . It also has a prominent role in promoting wakefulness . The orexin receptor (also referred to as the hypocretin receptor) is a rhodopsin-like G protein-coupled receptor that binds orexin. There are two subtypes; orexin receptor 1 (OX1) and orexin receptor 2 (OX2) .

This entry represents Orexin receptor 2, which is found throughout vertebrates and, like OX1, is expressed in brainstem and striatal nuclei, with additional expression in arousal promoting histaminergic nuclei . Both Orexin-A and B have nearly equal affinity for OX2 , and stimulate intracellular calcium levels through OX2-mediated induction of Gq and phospholipase C activity, but is also capable of activating Gs, Gi, and potentially ion channels . The OX2 receptor predominantly mediate the control of arousal induced by orexin neuropeptides .
CC chemokine receptor 6 (Chemokine_CCR6)
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).

CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.

This entry represents CC chemokine receptor 6 (CCR6). It is expressed on unactivated memory T-cells and some dendritic cells . CCR6 is also expressed on Th17 cells , but is down-regulated in activated T-cells . The receptor is noted as playing a role in Crohn's disease . CCR6 major ligand is CCL20, also known as Liver and Activation-Regulated Chemokine but it can also bind non-chemokine ligands such as beta-defensines . Binding to beta-defensine 1 (DEFB1) is essential for the function of DEFB1 in regulating sperm motility and bactericidal activity and it mediates the chemotactic effects of defensins DEFB4 and DEFB4A/B .
CC chemokine receptor 8 (Chemokine_CCR8)
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).

CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.

This entry represents CC chemokine receptor 8 (CCR8), which it is expressed predominantly in lymphoid tissues and has also been found in glomerular podocytes and human umbilical vein endothelial cells (HUVECs) . CCR8 is associated with Th2 lymphocytes, which are critical for allergy, and has a role in lymphocyte activation, migration, proliferation and differentiation and in allergic diseases . CCR8 binds to CCL1 (also known as I-309) and to CCL16 (also known as liver expressed chemokine) . It also exhibits a high affinity for three chemokines of viral origin: vMIP-I, vMIP-II and vMCC-I.
CC chemokine receptor 9 (Chemokine_CCR9)
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).

CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.

This entry represents CC chemokine receptor 9 (CCR9), which was previously designated as the orphan receptors GPR28 and GPR 9-6. CCR9 is expressed predominantly in the thymus, in both mature and immature T cells, and is also found in the lymph nodes, spleen, glomerular podocytes, bone marrow stromal cells and the small intestine . Transfected cells expressing CCR9 receptor bind specifically to CCL25 (also known as Thymus-Expressed Chemokine) . This interaction may play a pivotal role in T-cell migration in the thymus . CCR9 activation has also been shown to influence cancer cell migration, invasion and matrix metallopeptidase expression, which together may affect prostate cancer metastasis .
Cysteinyl leukotriene receptor (Cyst_leuk_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 .

Leukotrienes (LT) are potent lipid mediators derived from arachidonic acid metabolism. They can be divided into two classes based on the presence or absence of a cysteinyl group. Leukotriene B4 (LTB4) does not contain such a group, whereas LTC4, LTD4, LTE4 and LTF4 are cysteinyl leukotrienes.

Cysteinyl leukotrienes (CysLTs), previously known as the "slow reacting substance of anaphylaxis", are produced predominantly by myeloid cells associated with inflammatory responses . They are the most potent bronchoconstrictors known and also have pro-inflammatory effects, making them important mediators in the pathophysiology of human asthma . CysLTs have also been implicated in a variety of other diseases, such as allergic rhinitis, inflammatory bowel disease and psoriasis . Pharmacological studies of the effects of CysLTs have provided evidence for the existence of at least 2 distinct receptor subtypes, belonging to the G protein-coupled receptor family, designated CysLT1 and CysLT2 . CysLT1 is thought to mediate bronchospasm, plasma exudation, vasoconstriction, mucus secretion and eosinophil recruitment . CysLT2 is less well defined, due to a lack of specific agonists and antagonists, but is thought to mediate some of the vascular effects attributed to CysLTs . Both receptor subtypes have now been cloned .
Interleukin-1 receptor type I/II (IL-1_rcpt_I/II-typ)
Type: Family

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis . Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors . The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location . The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).

The crystal structures of IL1A and IL1B have been solved, showing them to share the same 12-stranded β-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors . The β-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel β-barrel. Several regions, especially the loop between strands 4 and 5, have been implicated in receptor binding.

The Vaccinia virus genes B15R and B18R each encode proteins with N-terminal hydrophobic sequences, possible sites for attachment of N-linked carbohydrate and a short C-terminal hydrophobic domain . These properties are consistent with the mature proteins being either virion, cell surface or secretory glycoproteins. Protein sequence comparisons reveal that the gene products are related to each other (20% identity) and to the Ig superfamily. The highest degree of similarity is to the human and murine interleukin-1 receptors, although both proteins are related to a wide range of Ig superfamily members, including the interleukin-6 receptor. A novel method for virus immune evasion has been proposed in which the product of one or both of these proteins may bind interleukin-1 and/or interleukin-6, preventing these cytokines reaching their natural receptors . A similar gene product from Cowpox virus (CPV) has also been shown to specifically bind murine IL-1 beta .

The crystal structure of the soluble extracellular part of type-I IL1R complexed with IL1RA has been determined to 2.7A resolution . The receptor structure is characterised by three Ig-like domains, of which domains 1 and 2 are tightly linked, while domain 3 is completely separate and connected by a flexible linker.
Interleukin-1 receptor type 1 (IL-1_rcpt_I-typ)
Type: Family

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis . Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors . The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location . The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).

The crystal structures of IL1A and IL1B have been solved, showing them to share the same 12-stranded β-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors . The β-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel β-barrel. Several regions, especially the loop between strands 4 and 5, have been implicated in receptor binding.

The Vaccinia virus genes B15R and B18R each encode proteins with N-terminal hydrophobic sequences, possible sites for attachment of N-linked carbohydrate and a short C-terminal hydrophobic domain . These properties are consistent with the mature proteins being either virion, cell surface or secretory glycoproteins. Protein sequence comparisons reveal that the gene products are related to each other (20% identity) and to the Ig superfamily. The highest degree of similarity is to the human and murine interleukin-1 receptors, although both proteins are related to a wide range of Ig superfamily members, including the interleukin-6 receptor. A novel method for virus immune evasion has been proposed in which the product of one or both of these proteins may bind interleukin-1 and/or interleukin-6, preventing these cytokines reaching their natural receptors . A similar gene product from Cowpox virus (CPV) has also been shown to specifically bind murine IL-1 beta .

This entry represents Interleukin-1 receptor type 1 (IL1R1), the crystal structure of the soluble extracellular part of type-I IL1R complexed with IL1RA has been determined to 2.7A resolution . The receptor structure is characterised by three Ig-like domains, of which domains 1 and 2 are tightly linked, while domain 3 is completely separate and connected by a flexible linker.