SII-SWORD/CoKE huggingface dataset:
Melatonin receptor family (Melatonin_rcpt)
Type: Family

Melatonin is a naturally occurring compound found in animals, plants, and microbes . In animals melatonin is secreted by the pineal gland during darkness . It regulates a variety of neuroendocrine functions and is thought to play an essential role in circadian rhythms . Drugs that modify the action of melatonin, and hence influence circadian cycles, are of clinical interest for example, in the treatment of jet-lag .

Many of the biological effects of melatonin are produced through the activation of melatonin receptors , which are members of rhodopsin-like G protein-coupled receptor family. There are three melatonin receptor subtypes. Melatonin receptor type 1A and melatonin receptor type 1B are present in humans and other mammals while melatonin receptor type 1C has been identified in amphibia and birds . There is also a closely-related orphan receptor, termed melatonin-related receptor type 1X (also known as GPR50) , 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. Melatonin receptor type 1C receptors are 80% identical and are distinct from 1A and 1B subtypes. Similar ligand binding and functional characteristics are observed in expressed 1A and 1C receptors. The melatonin receptors inhibit adenylyl cyclase via a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class.

This entry represents the melatonin receptor family.
Guanine-specific ribonuclease N1-like (N1-like)
Type: Family

This entry represents Guanyl-specific ribonuclease N1 from Neurospora crassa , and similar sequences from fungi and bacteria, including Ribonuclease

from Bacillus amyloliquefaciens (also known as Barnase) and Ribonuclease clavin from Aspergillus clavatus. Barnase hydrolyses the phosphodiester bonds in RNA and oligoribonucleotides , resulting in 3'-nucleoside monophosphates via 2',3'-cyclophosphate intermediates. Clavin has the same substrate specificity as alpha-sarcin. It is specific for purines in both single- and double-stranded RNA. Its toxic action on eukaryotic cells is the result of cleavage of a single phosphodiester bond in the 60S subunit of ribosomes .
Chloroperoxidase (Chloroperoxidase)
Type: Domain

Chloroperoxidase (CPO), also known as Heme haloperoxidase, is a ~250 residue heme-containing glycoprotein that is secreted by various fungi. Chloroperoxidase was first identified in Caldariomyces fumago where it catalyses the hydrogen peroxide-dependent chlorination of cyclopentanedione during the biosynthesis of the antibiotic caldarioymcin. Additionally, Heme haloperoxidase catalyses the iodination and bromination of a wide range of substrates. Besides performing H2O2-dependent halogenation reactions, the enzyme catalyses dehydrogenation reactions. Chloroperoxidase also functions as a catalase, facilitating the decomposition of hydrogen peroxide to oxygen and water. Furthermore, chloroperoxidase catalyses P450-like oxygen insertion reactions. The capability of chloroperoxidase to perform these diverse reactions makes it one of the most versatile of all known heme proteins .

Despite functional similarities with other heme enzymes, chloroperoxidase folds into a novel tertiary structure dominated by eight helical segments . Structurally, chloroperoxidase is unique, but it shares features with both peroxidases and P450 enzymes. As in cytochrome P450 enzymes, the proximal heme ligand is a cysteine, but similar to peroxidases, the distal side of the heme is polar. However, unlike other peroxidases, the normally conserved distal arginine is lacking and the catalytic acid base is a glutamic acid and not a histidine .
PPE domain (PPE_dom)
Type: Domain

The human pathogen Mycobacterium tuberculosis harbours a large number of genes that encode proteins whose N-terminals contain the characteristic motifs Pro-Glu (PE) or Pro-Pro-Glu (PPE). These proteins are exported to the bacterial surface via type VII secretion systems known as ESX . A subgroup of the PE proteins contains polymorphic GC-rich sequences (PGRS), while a subgroup of the PPE proteins contains major polymorphic tandem repeats (MPTR). The function of most of these proteins remains unknown . However, the PE_PGRS proteins from Mycobacterium marinum are secreted by components of the ESX-5 system that belongs to the recently defined type VII secretion systems . It has also been reported that the PE_PGRS family of proteins contains multiple calcium-binding and glycine-rich sequence motifs GGXGXD/NXUX. This sequence repeat constitutes a calcium-binding parallel β-roll or parallel β-helix structure and is found in RTX toxins secreted by many Gram-negative bacteria .

PPE51 member has been described as a small molecule-selective channel required for the uptake of nutrients across the outer mycomembrane . This protein transports glycerol and glucose as well as maltose and lactose disaccharides. It is involved in sensitivity to M.tuberculosis growth inhibitory agrichemical 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) and sensitivity to bactericidal thio-disaccharide T-6 compound .

This entry represents a domain found in proteins from actinomycetes named after a conserved N-terminal region of about 180 amino acids, the PPE motif. The C-terminal end of proteins belonging to the PPE family is variable, and on the basis of this region at least three groups can be distinguished. The MPTR subgroup is characterised by tandem copies of a motif NXGXGNXG. The second subgroup contains a conserved motif at about position 350. The third group shares only similarity in the amino terminal region. The function of these proteins is uncertain but it has been suggested that they may be related to antigenic variation of Mycobacterium tuberculosis . Some members of this family are associated with virulence and evasion of host immune response as they have a role in preventing ROS generation .
PurE domain (PurE_dom)
Type: Domain

The novo purine biosynthesis proceeds by two divergent paths. In bacteria, yeasts, and plants, 5-aminoimidazole ribonucleotide (AIR) is converted to 4-carboxy-AIR (CAIR) by two enzymes: N5-carboxy-AIR (N5-CAIR) synthetase (PurK) and N5-CAIR mutase (class I PurE). In animals, the conversion of AIR to CAIR requires a single enzyme, AIR carboxylase (class II PurE) . Class I and class II PurEs are mechanistically related but bind different substrates. In yeast and plants PurE is found in PurK-class I PurE fusion proteins, known as ADE2 , while animal class II PurEs are found in PurC-PurE fusion proteins, also known as ADE2 or PAICS .
Phosphocarrier protein HPr-like (HPr-like)
Type: Domain

This entry represents a structural domain found in both the histidine-containing phosphocarrier protein HPr, as well as its structural homologues, which includes the catabolite repression protein Crh found in Bacillus subtilis . This domain has a α+β structure found in two layers with an overall architecture of an open faced β-sandwich in which a β-sheet is packed against three α-helices.
LDLR class B repeat (LDLR_classB_rpt)
Type: Repeat

The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes, while the receptor returns to the cell surface . The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing:

The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation . Similar domains have been found in other extracellular and membrane proteins .

The second conserved region contains two EGF repeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a β-propeller structure . This region is critical for ligand release and recycling of the receptor .

The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.

The fourth domain is the hydrophobic transmembrane region.

The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.

LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins .

This entry represents the LDLR classB (YWTD) repeat, the structure of which has been solved . The six YWTD repeats together fold into a six-bladed β-propeller. Each blade of the propeller consists of four antiparallel β-strands; the innermost strand of each blade is labeled 1 and the outermost strand, 4. The sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue YWTD repeat spans strands 24 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 24 from the first sequence repeat. The repeat is found in a variety of proteins that include, vitellogenin receptor from Drosophila melanogaster, low-density lipoprotein (LDL) receptor , preproepidermal growth factor, and nidogen (entactin).
Laminin IV (Laminin_IV)
Type: Domain

Laminin is a large molecular weight glycoprotein present only in basement membranes in almost every animal tissue. Each laminin is a heterotrimer assembled from alpha, beta and gamma chain subunits, secreted and incorporated into cell-associated extracellular matrices. The laminins can self-assemble, bind to other matrix macromolecules, and have unique and shared cell interactions mediated by integrins, dystroglycan, and other receptors. Through these interactions, laminins critically contribute to cell differentiation, shape and movement, maintenance of tissue phenotypes, and promotion of tissue survival .

The different laminin chains share a 600-residue domain I/II which oligomerises into a rod-like coiled-coil structure forming the long arm of laminins. The N-terminal short arms consist of rod-like elements (domain III and V) formed by tandem arrays of laminin-type EGF modules and several globular domains: domains IV and domain VI (laminin N-terminal). All alpha chains share a unique C-terminal G domain which consists of five laminin G modules . Laminin IV domain is also found in the perlecan protein, an integral component of basement membranes, which serves also as an attachment substrate for cells, but it is not found in short laminin chains (alpha4 or beta3). The function of this domain is not yet known.
Alkylbase DNA glycosidase, conserved site (Alkylbase_DNA_glycsylse_CS)
Type: Conserved_site

Alkylbase DNA glycosidases are DNA repair enzymes that hydrolyse the deoxyribose N-glycosidic bond to excise various alkylated bases from a damaged DNA polymer. In Escherichia coli there are two alkylbase DNA glycosidases: one (gene tag) which is constitutively expressed and which is specific for the removal of 3-methyladenine (

), and one (gene alkA) which is induced during adaptation to alkylation and which can remove a variety of alkylation products (

). Tag and alkA do not share any region of sequence similarity. In yeast there is an alkylbase DNA glycosidase (gene MAG1) , which can remove 3-methyladenine or 7-methyladenine and which is structurally related to alkA. MAG and alkA are both proteins of about 300 amino acid residues. While the C- and N-terminal ends appear to be unrelated, there is a central region of about 130 residues which is well conserved.
SsrA-binding protein (SsrA-bd_prot)
Type: Family

This entry represents SsrA-binding protein (aka small protein B or SmpB), which is a unique RNA-binding protein that is conserved throughout the bacterial kingdom and is an essential component of the SsrA quality-control system. Tight recognition of codon-anticodon pairings by the ribosome ensures the accuracy and fidelity of protein synthesis. In eubacteria, translational surveillance and ribosome rescue are performed by the 'tmRNA-SmpB' system (transfer messenger RNA-small protein B). SmpB binds specifically to the ssrA RNA (tmRNA) and is required for stable association of ssrA with ribosomes. SsrA RNA recognises ribosomes stalled on defective messages and acts to mediate the addition of a short peptide tag to the C terminus of the partially synthesised nascent polypeptide chain. Within a stalled ribosome, SmpB interacts with the three universally conserved bases G530, A1492 and A1493 that form the 30S subunit decoding centre, in which canonical codon-anticodon pairing occurs . The SsrA-tagged protein is then degraded by C-terminal-specific proteases. Formation of an SmpB-SsrA complex appears to be critical in mediating SsrA activity after aminoacylation with alanine but prior to the transpeptidation reaction that couples this alanine to the nascent chain . The SmpB protein has functional and structural similarities with initiation factor 1, and is proposed to be a functional mimic of the pairing between a codon and an anticodon.
Large ribosomal subunit protein eL18 (Ribosomal_eL18)
Type: Family

Members of this family are large subunit ribosomal proteins which are found in eukaryotes and archaea . These proteins have 115 to 187 amino-acid residues. The family consists of:

Vertebrate eL18 (known as L14 in Xenopus)

Plant eL18

Yeast eL18 (Rp28)

Haloarcula marismortui (Halobacterium marismortui) HL29

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 .
Adenosylhomocysteinase-like (Adenosylhomocysteinase-like)
Type: Family

Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase,

) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. This enzyme is ubiquitous, highly conserved, and may play a key role in the regulation of the intracellular concentration of adenosylhomocysteine. AdoHcyase requires NAD+ as a cofactor and contains a central glycine-rich region which is thought to be involved in NAD-binding. Since AdoHyc is a potent inhibitor of S-adenosyl-L-methionine dependent methyltransferases, AdoHycase plays a critical role in the modulation of the activity of various methyltransferases. The enzyme forms homotetramers, with each monomer binding one molecule of NAD+ .

This family also includes S-adenosylhomocysteine hydrolase-like 1 (Ahcyl1), also known as IRBIT, and S-adenosylhomocysteine hydrolase-like protein 2 (Ahcyl2). Ahcyl1/IRBIT was shown to interact with inositol 1,4,5-trisphosphate receptors (IP3Rs), which function as intracellular Ca(2+) channels, and suppresses IP3 binding of IP3R . By competing with IP3, it modulates the threshold IP3 concentration required for the activation of the receptor . Further studies indicate that Ahcyl1/IRBIT is in fact a multifunctional protein that regulates several ion channels and ion transporters . Despite its homology to S-adenosylhomocysteine hydrolases, Ahcyl1 has neither enzyme activity nor any effects on the enzyme activity of S-adenosylhomocysteine hydrolase . Ahcyl2 lacks binding activity to IP3R . Ahcyl2 upregulates NBCe1-B, which plays an important role in intracellular pH regulation .
Uncharacterised lipoprotein MG045 (Uncharacterised_lipoprot_MG045)
Type: Family

Mycoplasma genitalium has the smallest known genome of any free-living organism. Its complete genome sequence has been determined by whole-genome random sequencing and assembly . Only 470 putative coding regions were identified, including genes for DNA replication, transcription and translation, DNA repair, cellular transport and energy metabolism . A hypothetical protein from the MG045 gene has a homologue of similarly unknown function in M.pneumoniae; these, in turn, share regions of similarity with a family of putative lipoproteins from Ureaplasma parvum and Ureaplasma urealyticum.
Neurokinin NK1 receptor (NK1_rcpt)
Type: Family

This entry represents Neurokinin 1 (NK1) receptor that is involved in inflammation and pain transmission. It binds substance P, the first neuropeptide to be discovered in mammals. Neuropeptide receptors are present in very small quantities in the cell and are embedded tightly in the plasma membrane. The neuropeptides exhibit a high degree of functional diversity through both regulation of peptide production and through peptide-receptor interaction . The mammalian tachykinin system consists of 3 distinct peptides: substance P, substance K and neuromedin K. All possess a common spectrum of biological activities, including sensory transmission in the nervous system and contraction/ relaxation of peripheral smooth muscles, and each interacts with a specific receptor type.

Biological functionality of substance P is mediated by its interaction with NK1 receptor, which is a member of GPCR family. In the brain, high concentrations of the NK1 receptor are found in striatum, olfactory bulb, dendate gyrus, locus coeruleus and spinal chord . In peripheral tissues NK1 receptors are found in smooth muscle (e.g., ileum and bladder), enteric neurons, secretory glands (e.g. parotid), cells of the immune system and vascular endothelium. NK1 receptors activate the phosphoinositide pathway through a pertussis-toxin-insensitive G-protein .

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 .

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 .
IQ motif, EF-hand binding site (IQ_motif_EF-hand-BS)
Type: Binding_site

The IQ motif is an extremely basic unit of about 23 amino acids, whose conserved core usually fits the consensus A-x(3)-I-Q-x(2)-F-R-x(4)-K-K. The IQ motif, which can be present in one or more copies, serves as a binding site for different EF-hand proteins, including the essential and regulatory myosin light chains, calmodulin (CaM), CaM-like proteins and Neuromodulin . Many IQ motifs are protein kinase C (PKC) phosphorylation sites .

Resolution of the 3D structure of scallop myosin has shown that the IQ motif forms a basic amphipathic helix .

Some proteins known to contain an IQ motif are listed below:

A number of conventional and unconventional myosins.

Neuromodulin (GAP-43). This protein is associated with nerve growth. It is a major component of the motile "growth cones" that form the tips of elongating axons.

Neurogranin (NG/p17). Acts as a "third messenger" substrate of protein kinase C-mediated molecular cascades during synaptic development and remodeling.

Sperm surface protein Sp17.

Ras GTPase-activating-like protein IQGAP1. IQGAP1 contains 4 IQ motifs.

This entry covers the entire IQ motif.
Electron transfer flavoprotein, beta-subunit, conserved site (ET-Flavoprotein_bsu_CS)
Type: Conserved_site

The electron transfer flavoprotein (ETF) serves as a specific electron acceptor for various mitochondrial dehydrogenases. ETF transfers electrons to the main respiratory chain via ETF-ubiquinone oxidoreductase. ETF is an heterodimer that consist of an alpha and a beta subunit and which bind one molecule of FAD per dimer. A similar system also exists in some bacteria. The beta subunit of ETF is a protein of about 28 Kd which is structurally related to the bacterial nitrogen fixation protein fixA which could play a role in a redox process and feed electrons to ferredoxin. The beta subunit protein is distantly related to and forms a heterodimer with the alpha subunit

.
Potex/carlavirus coat protein (Pltvir_coat)
Type: Domain

Potexviruses and Carlaviruses are plant-infecting viruses whose genome consist of a single-stranded RNA molecule encapsided in a coat protein. The genome of many Potexviruses is known and their coat protein sequence has been shown to be rather well conserved . The same observation applies to the coat protein of a variety of Carlaviruses whose sequences are related to those of Potexviruses . The coat proteins of Potexviruses and of Carlaviruses contain from 190 to 300 amino acid residues. The best conserved region of these coat proteins is located in the central part.