SII-SWORD/CoKE huggingface dataset:
GPCR family 3, C-terminal (GPCR_3_C)
Type: Domain

This entry represents the C-terminal region of family 3 GPCR receptor proteins, which contains the seven transmembrane region. The seven TM regions assemble in such a way as to produce a docking pocket into which such molecules as cyclamate and lactisole have been found to bind and consequently confer the taste of sweetness .

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 .

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.
GPCR, family 3, conserved site (GPCR_3_CS)
Type: Conserved_site

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 .

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

This entry represents three conserved sites found in family 3 GPCR receptor proteins. The first conserved site is centred around a highly conserved hydrophobic segment in the central part of the N-terminal extracellular region; the second conserved site is centred around a cluster of six cysteines in the C-terminal part of the extracellular domain; the third conserved site is centred around the C-terminal part of the cytoplasmic loop between the fifth and sixth transmembrane domains.
Metallothionein, family 4, echinoidea/annelida (Metalthion_4_echinoid/annelid)
Type: Family

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds . An empirical classification into three classes has been proposed by Fowler and coworkers and Kojima . Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,
fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units .

This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms .

Echinoidea (sea urchin, family 4) MTs are 64-67 residue proteins. Members of this family are recognised by the sequence pattern P-D-x-K-C-[V,F]-C-C-x(5)-C-x-C-x(4)-C-C-x(4)-C-C-x(4,6)-C-C located near the N terminus.
The taxonomic range of the members extends to sea urchins (echinodea).
The protein sequence is divided into two structural domains, each containing 9 and 11 Cys residues binding 3 and 4 bivalent metal ions, respectively.
Family 4 includes subfamilies: e1, e2, they are separate phylogenetic groups.

This entry includes the sea urchin proteins, and related sequences from worms.
GPCR, family 2-like, 7TM (GPCR_2-like_7TM)
Type: Domain

This entry represents the transmembrane domain of family 2 GPCR receptor proteins and Frizzled proteins.

The secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

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 .
Defensin, insect (Defensin_insect)
Type: Family

Insect defensins are a diverse family of anti-bacterial peptides, largely active against Gram-positive bacteria . All these peptides range in length from 38 to 51 amino acids. There are six conserved cysteines all involved in intrachain disulphide bonds.

A schematic representation of peptides from the arthropod defensin family is shown below.

+----------------------------+
| |
xxCxxxxxxxxxxxxxxCxxxCxxxxxxxxxCxxxxxCxCxx
| | | |
+---|---------------+ |
+-----------------+

'C': conserved cysteine involved in a disulphide bond.

Although low level sequence similarities have been reported between the insect defensins and mammalian defensins, the topological arrangement of the disulphide bonds as well as the tertiary structure are completely different in the two families.

A member of this family, coprisin, is a potent broad-spectrum antibacterial peptide against both Gram-positive and Gram-negative bacteria , also active against all antibiotic-resistant bacterial strains tested , which acts through the permeabilization of the bacterial cell membrane . It can induce apoptosis in C.albicans, without disrupting the fungal plasma membrane . This defensin also shows potent anti-inflammatory activities, since it reduces both LPS-induced nitric oxide release and proinflammatory cytokine production . The anti-inflammatory activities are initiated by suppressing the binding of LPS to toll-like receptor 4 (TLR4), and subsequently inhibiting the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear translocation of NF-kB (TNFRSF11A) . This defensin is an interesting antibacterial compound that does not show hemolytic activity against human erythrocytes and does not affect human cell membranes .
GPCR, family 2, secretin-like, conserved site (GPCR_2_secretin-like_CS)
Type: Conserved_site

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 secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

This entry represents a pair of conserved sites found within family 2 GPCR receptor proteins. The first conserved site spans three of the five highly conserved cysteine residues found within the N-terminal extracellular domain that may be involved in disulphide bonds. The second conserved site within a region spanning the C-terminal part of the last transmembrane region and the beginning of the adjacent intracellular region.
Chromo domain subgroup (Chromo_dom_subgr)
Type: Domain

The CHROMO (CHRromatin Organization MOdifier) domain is a conserved region of around 60 amino acids, originally identified in Drosophila modifiers of variegation.
These are proteins that alter the structure of chromatin to the condensed morphology of heterochromatin, a cytologically visible condition where gene expression is repressed. In one of these proteins, Polycomb, the chromo domain has been shown to be important for chromatin targeting. Proteins that contain a chromo domain appear to fall into 3 classes. The first class includes proteins having an N-terminal chromo domain followed by a region termed the chromo shadow domain , eg. Drosophila and human heterochromatin protein Su(var)205 (HP1). The second class includes proteins with a single chromo domain, eg. Drosophila protein Polycomb (Pc); mammalian modifier 3; human Mi-2 autoantigen and and several yeast and Caenorhabditis elegans hypothetical proteins. In the third class paired tandem chromo domains are found, eg. in mammalian DNA-binding/helicase proteins CHD-1 to CHD-4 and yeast protein CHD1.

This entry represents a subgroup of the Chromo domai
DNA methylase, N-4 cytosine-specific, conserved site (MeTrfase_CN4_CS)
Type: Conserved_site

Synonym(s): N-4 cytosine-specific DNA methylase, Modification methylase

Site-specific DNA-methyltransferase (cytosine-N4-specific) (

) are enzymes that specifically methylate the amino group at the C-4 position of cytosines in DNA. In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. There are two major classes of DNA methyltransferase that differ in the nature of the modifications they effect. The members of one class (C-MTases) methylate a ring carbon and form C5-methylcytosine and members of the second class (N-MTases) methylate exocyclic nitrogens and form either N4-methylcytosine (N4-MTases) or
N6-methyladenine (N6-MTases). Both classes of MTase utilise the cofactor
S-adenosyl-L-methionine (SAM) as the methyl donor and are active as monomeric enzymes .
Ribosome-inactivating protein type 1/2 (Ribosome_inactivat_1/2)
Type: Family

A number of bacterial and plant toxins act by inhibiting protein synthesis in eukaryotic cells. The toxins of the shiga and ricin family inactivate 60S ribosomal subunits by an N-glycosidic cleavage which releases a specific adenine base from the sugar-phosphate backbone of 28S rRNA . Members of the family include shiga and shiga-like toxins, and type I (e.g. trichosanthin and luffin) and type II (e.g. ricin, agglutinin and abrin) ribosome inactivating proteins (RIPs). All these toxins are structurally related. RIPs have been of considerable interest because of their potential use, conjugated with monoclonal antibodies, as immunotoxins to treat cancers. Further, trichosanthin has been shown to have potent activity against HIV-1-infected T cells and macrophages . Elucidation of the structure-function relationships of RIPs has therefore become a major research effort. It is now known that RIPs are structurally related. A conserved glutamic residue has been implicated in the catalytic mechanism ; this lies near a conserved arginine, which also plays a role in catalysis .

This entry represents type I and type II RIPs. It does not include shiga and shiga-like toxins.
Atrophin-1 (Atrophin-1)
Type: Family

Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins . The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteristic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity .

.
P-type trefoil, chordata (P_trefoil_chordata)
Type: Family

A cysteine-rich domain of approximately forty five amino-acid residues has been found in some extracellular eukaryotic proteins . It is known as either the 'P', 'trefoil' or 'TFF' domain, and contains six cysteines linked by three disulphide bonds with connectivity 1-5, 2-4, 3-6. This leads to a characteristic three leafed structure ('trefoil'). The P-type domain is clearly composed of three looplike regions. The central core of the domain consists of a short two-stranded antiparallel β-sheet, which is capped by an irregular loop and forms a central hairpin (loop 3). The β-sheet is preceded by a short α-helix, with majority of the remainder of the domain contained in two loops, which lie on either side of the central hairpin.

This domain has been found in a variety of extracellular eukaryotic proteins , including:

Protein pS2 (TFF1), a protein secreted by the stomach mucosa

Spasmolytic polypeptide (SP) (TFF2), a protein of about 115 residues that inhibits gastrointestinal motility and gastric acid secretion

Intestinal trefoil factor (ITF) (TFF3)

Xenopus laevis stomach proteins xP1 and xP4

Xenopus integumentary mucins A.1 (FIM-A.1 or preprospasmolysin) and C.1 (FIM-C.1), proteins which may be involved in defence against microbial infections by protecting the epithelia from the external environment

Xenopus skin protein xp2 (or APEG)

Zona pellucida sperm-binding protein B (ZP-B)

Intestinal sucrase-isomaltase (

/

), a vertebrate membrane bound, multifunctional enzyme complex which hydrolyses sucrose, maltose and isomaltose

Lysosomal alpha-glucosidase (

)
Homeobox protein, antennapedia type (Homeobox_antennapedia)
Type: Family

The homeobox is a 60-residue motif first identified in a number of Drosophila homeotic and segmentation proteins, but now known to be well-conserved in many other animals, including vertebrates . Proteins containing homeobox domains are likely to play an important role in development - most are known to be sequence-specific DNA-binding transcription factors. The domain binds DNA through a helix-turn-helix (HTH) structure.

Many homeodomain-containing proteins have now been sequenced and, while the homeodomain flanking regions vary, characteristic conserved sequences upstream of the domain allow the proteins to be grouped into 3 subfamilies: the so-called antennapedia, engrailed and 'paired box' proteins. Antennapedia, which regulates the formation of leg structures in Drosophila, was one of the first homeotic genes studied and led to the discovery of the homeobox domain. Over expression of this gene in the wrong segment of the fruit fly can lead to the formation of leg structures in these segments. For example, over expression in the head segment can lead to the formation of legs instead of antennae (hence the name antennapedia). The sequences of the antennapedia proteins contain a conserved hexapeptide 5-16 residues upstream of the homeobox, the specific function of which is unclear. The six Drosophila proteins that belong to this group are antennapedia (Antp), abdominal-A (abd-A), deformed (Dfd), proboscipedia (pb), sex combs reduced (scr) and ultrabithorax (ubx) and are collectively known as the 'antennapedia' subfamily.

In vertebrates the corresponding Hox genes are known as Hox-A2, A3, A4, A5, A6, A7, Hox-B1, B2, B3, B4, B5, B6, B7, B8, Hox-C4, C5, C6, C8, Hox-D1, D3, D4 and D8.

Caenorhabditis elegans lin-39 and mab-5 are also members of the 'antennapedia' subfamily.

Arg and Lys are most frequently found in the last position of the hexapeptide; other amino acids are found in only a few cases.
Major royal jelly/yellow-related (MRJP/yellow-related)
Type: Family

This family describes major royal jelly protein and other yellow-related proteins mostly found in insects. It includes dopaminechrome tautomerase (DPT) which is enconded by the yellow-h gene in Drosophila. DPT catalyzes the conversion of dopaminechrome to 5,6-dihydroxyindole in the eumelanin biosynthetic pathway originating from dopamine . It also includes putative gluconolactonase proteins and yellow-related proteins proteins from fungi and prokaryotic organisms.

The major royal jelly proteins (MRJPs) comprise 12.5% of the mass, and 82-90% of the protein content , of honeybee (Apis mellifera) royal jelly. Royal jelly is a substance secreted by the cephalic glands of nurse bees and it is used to trigger development of a queen bee from a bee larva. The biological function of the MRJPs is unknown, but they are believed to play a major role in nutrition due to their high essential amino acid content . Two royal jelly proteins, MRJP3 and MRJP5, contain a tandem repeat that results from a high genetic variability. This polymorphism may be useful for genotyping individual bees .

Yellow-related salivary proteins in sand flies are a conserved family of proteins with significant roles in host interactions and disease pathogenesis. These proteins exhibit neutrophil chemoattractant properties in vitro and in vivo, recruiting immune cells to bite sites via dose-dependent chemotaxis. Structurally, they adopt a six-bladed β-propeller fold with a ligand-binding pocket capable of high-affinity interactions with biogenic amines (e.g., serotonin, histamine) to modulate hemostasis and inflammation . Yellow proteins also include yellow-f and yellow-f2 proteins from Drosophila, which are dopachrome-conversion enzymes responsible for catalysing the conversion of dopachrome into 5,6-dihydroxyindole in the melanisation pathway .