SII-SWORD/CoKE huggingface dataset:
Thrombin receptor (Thrmbn_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 .

Thrombin is a serine protease with a central role in blood clotting. It cleaves various substrates involved in coagulation, and activates cell surface receptors via a novel proteolytic action. Thrombin stimulates aggregation and secretion in blood platelets at the site of vascular injury, and also has inflammatory and reparative actions, stimulating chemotaxis in monocytes, proliferation of fibroblasts and lymphocytes, and inducing endothelium-dependent relaxation of blood vessels. The protein activates a number of substrates involved in coagulation: it cleaves fibrinogen to fibrin and activates coagulation factor XIII; it also activates factors V and VIII. When bound to thrombomodulin, it activates plasma protein C, which, in concert with protein S, inactivates factors Va and VIIIa, leading to a decrease in thrombin formation.

The thrombin receptor is expressed in high levels in platelets, vascular endothelial cells, and various cell lines. The receptor activates phosphoinositide metabolism via a pertussis-toxin-insensitive G-protein, and inhibits adenylyl cyclase via a pertussis-toxin-sensitive G-protein.
Alphavirus E2 glycoprotein (Alpha_E2_glycop)
Type: Family

Alphaviruses are enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include Semliki Forest and Sindbis viruses . Alphaviruses consist of three structural proteins: the core nucleocapsid protein C, and the envelope proteins P62 and E1 (

) that associate as a heterodimer. The viral membrane-anchored surface glycoproteins are responsible for receptor recognition and entry into target cells through membrane fusion. The proteolytic maturation of P62 into E2 and E3 (

) causes a change in the viral surface. Together the E1, E2, and sometimes E3 glycoprotein "spikes" form an E1/E2 dimer or an E1/E2/E3 trimer, where E2 extends from the centre to the vertices, E1 fills the space between the vertices, and E3, if present, is at the distal end of the spike . Upon exposure of the virus to the acidity of the endosome, E1 dissociates from E2 to form an E1 homotrimer, which is necessary for the fusion step to drive the cellular and viral membranes together . This entry represents the alphaviral E2 glycoprotein. The E2 glycoprotein functions to interact with the nucleocapsid through its cytoplasmic domain, while its ectodomain is responsible for binding a cellular receptor.
Icosahedral viral capsid protein, S domain (Capsid_prot_S-dom_vir)
Type: Domain

The capsid proteins of plant icosahedral positive strand RNA viruses form 4 different domains, a positively charged, N-terminal 'R' domain, which interacts with RNA (66 residues); a connecting arm, 'a' (35 residues); a central, surface 'S' domain, which forms the virion shell; and a projecting, C-terminal 'P' domain . Some of the viruses lack either the R or P domains. The S domain contains from 158 to 166 amino acids and comprises 8 anti-parallel β-strands, which form a twisted sheet or jelly-roll fold. This structure is shared by a number of plant viral capsid proteins, which include: Carmovirus, Dianthovirus, Sobemovirus, Tombusvirus and an unidentified tobacco necrosis virus .
CAP Gly-rich domain (CAP-Gly_domain)
Type: Domain

Cytoskeleton-associated proteins (CAPs) are involved in the organisation of microtubules and transportation of vesicles and organelles along the cytoskeletal network. A conserved glycine-rich domain, CAP-Gly, has been identified in a number of CAPs, including CLIP-170 and dynactins. The crystal structure of the Caenorhabditis elegans F53F4.3 protein CAP-Gly domain has been solved. The domain contains three β-strands. The most conserved sequence, GKNDG, is located in two consecutive sharp turns on the surface, forming the entrance to a groove .
Adenoviral fibre protein, repeat/shaft region (Adenobir_fibre_prot_rpt/shaft)
Type: Repeat

Adenoviruses are responsible for diseases such as pneumonia, cystitis, conjunctivitis and diarrhoea, all of which can be fatal to patients who are immunocompromised . Viral infection commences with recognition of host cell receptors by means of specialised proteins on viral surfaces. Specific attachment of adenovirus is achieved through interactions between host-cell receptors and the adenovirus fibre protein and is mediated by the globular carboxy-terminal domain of the adenovirus fibre protein, rather than the 'shaft' region represented by this family. The alignment of this family contains two copies of a fifteen residue repeat found in the 'shaft' region of adenoviral fibre proteins.
Methyltransferase, NNMT/PNMT/TEMT (NNMT_TEMT_trans)
Type: Family

Methyl transfer from the ubiquitous S-adenosyl-L-methionine (AdoMet) to either nitrogen, oxygen or carbon atoms is frequently employed in diverse organisms ranging from bacteria to plants and mammals. The reaction is catalysed by methyltransferases (Mtases) and modifies DNA, RNA, proteins and small molecules, such as catechol for regulatory purposes. The various aspects of the role of DNA methylation in prokaryotic restriction-modification systems and in a number of cellular processes in eukaryotes including gene regulation and differentiation is well documented.

Three classes of DNA Mtases transfer the methyl group from AdoMet to the target base to form either N-6-methyladenine, or N-4-methylcytosine, or C-5-methylcytosine. In C-5-cytosine Mtases, ten conserved motifs are arranged in the same order . Motif I (a glycine-rich or closely related consensus sequence; FAGxGG in M.HhaI ), shared by other AdoMet-Mtases , is part of the cofactor binding site and motif IV (PCQ) is part of the catalytic site. In contrast, sequence comparison among N-6-adenine and N-4-cytosine Mtases indicated two of the conserved segments , although more conserved segments may be present. One of them corresponds to motif I in C-5-cytosine Mtases, and the other is named (D/N/S)PP(Y/F). Crystal structures are known for a number of Mtases . The cofactor binding sites are almost identical and the essential catalytic amino acids coincide. The comparable protein folding and the existence of equivalent amino acids in similar secondary and tertiary positions indicate that many (if not all) AdoMet-Mtases have a common catalytic domain structure. This permits tertiary structure prediction of other DNA, RNA, protein, and small-molecule AdoMet-Mtases from their amino acid sequences .

Several cytoplasmic vertebrate methyltransferases are evolutionary related , including nicotinamide N-methyltransferase (

) (NNMT); phenylethanolamine N-methyltransferase (

) (PNMT); and thioether S-methyltransferase (

) (TEMT). NNMT catalyses the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for the biotransformation of many drugs and xenobiotic compounds. PNMT catalyses the last step in catecholamine biosynthesis, the conversion of noradrenalin to adrenalin; and TEMT catalyses the methylation of dimethyl sulphide into trimethylsulphonium. These three enzymes use S-adenosyl-L-methionine as the methyl donor. They are proteins of 30 to 32kDa.
Enolase (Enolase)
Type: Family

Enolase (2-phospho-D-glycerate hydrolase) is an essential, homodimeric enzyme that catalyses the reversible dehydration of 2-phospho-D-glycerate to phosphoenolpyruvate as part of the glycolytic and gluconeogenesis pathways . The reaction is facilitated by the presence of metal ions . In vertebrates, there are 3 different, tissue-specific isoenzymes, designated alpha, beta and gamma. Alpha is present in most tissues, beta is localised in muscle tissue, and gamma is found only in nervous tissue. The functional enzyme exists as a dimer of any 2 isoforms. In immature organs and in adult liver, it is usually an alpha homodimer, in adult skeletal muscle, a beta homodimer, and in adult neurons, a gamma homodimer. In developing muscle, it is usually an alpha/beta heterodimer, and in the developing nervous system, an alpha/gamma heterodimer . The tissue specific forms display minor kinetic differences. Tau-crystallin, one of the major lens proteins in some fish, reptiles and birds, has been shown to be evolutionary related to enolase.

Neuron-specific enolase is released in a variety of neurological diseases, such as multiple sclerosis and after seizures or acute stroke. Several tumour cells have also been found positive for neuron-specific enolase. Beta-enolase deficiency is associated with glycogenosis type XIII defect.
Geminivirus AL2 coat protein, MSV type (Gemini_AL2)
Type: Family

Geminiviruses are characterised by a genome of circular single-stranded DNA encapsidated in twinned (geminate) quasi-isometric particles, from which the group derives its name . Most geminiviruses can be divided into two subgroups on the basis of host range and/or insect vector: i.e. those that infect dicotyledenous plants and are transmitted by the same whitefly species, and those that infect monocotyledenous plants and are transmitted by different leafhopper vectors. The genomes of the whitefly-transmitted African cassava mosaic virus, Tomato golden mosaic virus (TGMV) and Bean golden mosaic virus (BGMV) possess a bipartite genome. By contrast, only a single DNA component has been identified for the leafhopper-transmitted Maize streak virus (MSV) and Wheat dwarf virus (WDV) . Beet curly top virus (BCTV), and Tobacco yellow dwarf virus belong to a third possible subgroup. Like MSV and WDV, BCTV is transmitted by a specific leafhopper species, yet like the whitefly-transmitted geminiviruses it has a host range confined to dicotyledenous plants.

Sequence comparison of the whitefly-transmitted Squash leaf curl virus (SqLCV) and Tomato yellow leaf curl virus (TYLCV) with the genomic components of TGMV and BGMV reveals a close evolutionary relationship . Amino acid sequence alignments of Potato yellow mosaic virus (PYMV) proteins with those encoded by other geminiviruses show that PYMV is closely related to geminiviruses isolated from the New World, especially in the putative coat protein gene regions . Comparison of MSV DNA-encoded proteins with those of other geminiviruses infecting monocotyledonous plants, including Panicum streak virus and Miscanthus streak virus (MiSV) , reveal high levels of similarity.
RNA polymerase sigma-70 (RNA_pol_sigma70)
Type: Domain

The bacterial core RNA polymerase complex, which consists of five subunits, is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . RNA polymerase recruits alternative sigma factors as a means of switching on specific regulons. Most bacteria express a multiplicity of sigma factors. Two of these factors, sigma-70 (gene rpoD), generally known as the major or primary sigma factor, and sigma-54 (gene rpoN or ntrA) direct the transcription of a wide variety of genes. The other sigma factors, known as alternative sigma factors, are required for the transcription of specific subsets of genes.

With regard to sequence similarity, sigma factors can be grouped into two classes, the sigma-54 and sigma-70 families. Sequence alignments of the sigma70 family members reveal four conserved regions that can be further divided into subregions eg. sub-region 2.2, which may be involved in the binding of the sigma factor to the core RNA polymerase; and sub-region 4.2, which seems to harbor a DNA-binding 'helix-turn-helix' motif involved in binding the conserved -35 region of promoters recognised by the major sigma factors .

The plastids of higher plants originating from an ancestral cyanobacterial endosymbiont also contain sigma factors that are encoded by a small family of nuclear genes. All plastid sigma factors belong to the superfamily of sigmaA/sigma70 and have sequences homologous to the conserved regions 1.2, 2, 3, and 4 of bacterial sigma factors .

Each sigma2 domain is composed of a bundle of three α-helices that is virtually identical in all structures analyzed to date . The second helix of this bundle is a major point for contact with a coiled-coil domain in the beta' subunit of the core RNA polymerase complex. The third helix of the bundle includes conserved residues along one face that are involved in DNA melting and in recognition of the -10 promoter element. The sigma3 domain, which is less conserved between members of the sigma70 family is also a three-helix domain, the first helix of which contains the residues implicated in contacting DNA upstream of extended -10 promoters. The sigma4, domain has two pairs of α helices; the carboxy-terminal pair forms a helix-turn-helix motif that contacts the promoter DNA in the region from -30 to -38.
Transcription regulator Rrf2 (Tscrpt_reg_Rrf2)
Type: Family

This entry represents transcriptional regulators such as Desulfovibrio vulgaris Protein Rrf2, Escherichia coli IscR and Bacillus subtilis NsrR. Protein Rrf2 is a repressor of the hmc operon encoding a cytochrome redox complex for electron transport from hydrogen to sulphate . E. coli IscR regulates the transcription of several operons and genes involved in the biogenesis of Fe-S clusters and Fe-S-containing proteins . B. subtilis NsrR is a nitric oxide-responsive transcriptional regulator .
Dopamine beta-hydroxylase-like (DBH-like)
Type: Family

This family represents Dopamine beta-hydroxylase (DBH) and related enzymes, including tyramine beta-hydroxylase, MOXD1 homologue 1/2 and DBH-like monooxygenase protein 1/2 .

DBH, also known as Dopamine beta-hydroxylase, is a class of ascorbate-dependent enzymes from the catecholamine biosynthetic pathway that requires copper as a cofactor and uses ascorbate as an electron donor. DBH catalyses the conversion of dopamine to the neurotransmitter norepinephrine:

3,4-dihydroxyphenethylamine + ascorbate + O
2
= noradrenaline + dehydroascorbate + H
2
O

DBH exists in both soluble (in chromaffin granules) and membrane bound forms. The protein functions as a homotetramer .

This entry includes monooxigenases found in metazoans, plants and fungi.
ELM2 domain (ELM2_dom)
Type: Domain

The ELM2 (Egl-27 and MTA1 homology 2) domain is a small domain of unknown function. It is found in the MTA1 protein that is part of the NuRD complex . The domain is usually found to the N terminus of a myb-like DNA binding domain and a GATA binding domain. ELM2, in some instances, is also found associated with the ARID DNA binding domain

. This suggests that ELM2 may also be involved in DNA binding, or perhaps is a protein-protein interaction domain.
AB hydrolase 4, conserved site (AB_hydrolase_4_CS)
Type: Conserved_site

This entry represents a conserved site found in some of the AB hydrolase 4 family members, including mammalian ABHD1/2/3, budding yeast Eht1, Eeb1 and MGL2, and bacterial putative esterases.

Human ABHD3 is a phospholipase that may play a role in phospholipids remodeling. It may selectively cleave myristate (C14)-containing phosphatidylcholines through its predominant phospholipase 1 activity, cleaving preferentially acyl groups in sn1 position . Mouse ABHD2 may play a role in smooth muscle cells migration .
Chromo/chromo shadow domain (Chromo/chromo_shadow_dom)
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, with weak but significant sequence similarity to the N-terminal chromo 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 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.

Functional dissections of chromo domain proteins suggests a mechanistic role for chromo domains in targeting chromo domain proteins to specific regions of the nucleus. The mechanism of targeting may involve protein-protein and/or protein/nucleic acid interactions. Hence, several line of evidence show that the HP1 chromo domain is a methyl-specific histone binding module, whereas the chromo domain of two protein components of the drosophila dosage compensation complex, MSL3 and MOF, contain chromo domains that bind to RNA in vitro .

The high resolution structures of HP1-family protein chromo and chromo shadow domain reveal a conserved chromo domain fold motif consisting of three β-strands packed against an α-helix. The chromo domain fold belongs to the OB (oligonucleotide/oligosaccharide binding)-fold class found in a variety of prokaryotic and eukaryotic nucleic acid binding protein .
Stathmin family (Stathmin_fam)
Type: Family

Stathmin (from the Greek 'stathmos' which means relay), is a ubiquitous intracellular protein, present in a variety of phosphorylated forms. It is involved in the regulation of the microtubule (MT) filament system by destabilising microtubules. It prevents assembly and promotes disassembly of microtubules . However, when phosphorylated, its destabilisation ability is significantly reduced .
Sulphate/thiosulphate-binding, conserved site (Sulphate/thiosulphate-bd_CS)
Type: Conserved_site

Sulphate-binding protein (gene sbp or sbpA) and thiosulphate-binding protein (gene cysP) are two structurally related periplasmic bacterial proteins which specifically bind sulphate and thiosulphate and are involved in the transport systems for these nutrients . There are two conserved regions in the protein, one located in the N-terminal region and the other in the central part of these proteins. The second region includes two adjacent amino acids (Ser-Gly) that, in sbp, are known to be essential for sulphate binding .

This entry represents a conserved site located in the N-terminal region of these proteins.
POLO box domain (POLO_box_dom)
Type: Domain

A subgroup of serine/threonine protein kinases, Polo or Polo-like kinases play multiple roles during the cell cycle. Polo kinases are required at several key points through mitosis, starting from control of the G2/M transition through phosphorylation of Cdc25C and mitotic cyclins. They are also involved in meiosis I as regulators of kinetochore function . Polo kinases are characterised by an amino terminal catalytic domain, and a carboxy terminal non-catalytic domain consisting of three blocks of conserved sequences known as polo boxes which form one single functional domain . The domain is named after its founding member encoded by the polo gene of Drosophila melanogaster . This domain of around 70 amino acids has been found in species ranging from yeast to mammals. Polo boxes appear to mediate interaction with multiple proteins through protein:protein interactions; some but not all of these proteins are substrates for the kinase domain of the molecule .

The crystal structure of the polo domain of the murine protein, Sak, is dimeric, consisting of two α-helices and two six-stranded β-sheets . The topology of one polypeptide subunit of the dimer consists of, from its N-to C terminus, an extended strand segment, five β-strands, one α-helix (A) and C-terminal β-strand. β-strands from one subunit form a contiguous antiparallel β-sheet with β-strands from the second subunit. The two β-sheets pack with crossing angle of 110 degrees, orienting the hydrophobic surfaces inward and the hydrophilic surfaces outward. Helix A, which is colinear with β-strand 6 of the same polypeptide, buries a large portion of the non-overlapping hydrophobic β-sheet surfaces. Interactions involving helices A comprise a majority of the hydrophobic core structure and also the dimer interface.

Point mutations in the Polo box of the budding yeast Cdc5 protein abolish the ability of overexpressed Cdc5 to interact with the spindle poles and to organise cytokinetic structures .
Flavin monooxygenase FMO (Flavin_mOase)
Type: Family

Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-metabolising enzymes . Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorus and selenium atoms in a range of structurally diverse compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants. In man, lack of hepatic FMO-catalysed trimethylamine metabolism results in trimethylaminuria (fish odour syndrome). Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 . This is a recent nomenclature based on comparison of amino acid sequences, and has been introduced in an attempt to eliminate confusion inherent in multiple, laboratory-specific designations and tissue-based classifications . Following the determination of the complete nucleotide sequence of Saccharomyces cerevisiae (Baker's yeast) , a novel gene was found to encode a protein with similarity to mammalian monooxygenases. In Aspergillus, flavin-containing monooxygenases ustF1 and ustF2 are components in the biosynthesis of the antimitotic tetrapeptide ustiloxin B, a secondary metabolite. The monooxygenases modify the side chain of the intermediate S-deoxyustiloxin H .