SII-SWORD/CoKE huggingface dataset:
HTH ArsR-type DNA-binding domain (HTH_ArsR_DNA-bd_dom)
Type: Domain

The ArsR-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain present in transcription regulators of the ArsR/SmtB family, involved in stress-response to heavy metal ions. This family of prokaryotic metal-sensing transcription repressors is named after Escherichia coli ArsR, an arsenic-responsive repressor of the ars operon for arsenate reductase and metal ion extrusion, and after Synechococcus PCC 7942 SmtB, a Zn(II)-responsive repressor of the smtA gene for a Zn sequestering metallothionein . ArsR/SmtB-like repressors of metal resistance operons specifically bind to the operator/promoter and seem to dissociate from the DNA in the presence of metal ions, permitting transcription of proteins involved in metal-ions efflux and/or detoxification.

The crystal structure of the cyanobacterial smtB shows a fold of five α-helices (H) and a pair of antiparallel β-strands (B) in the topology H1-H2-H3-H4-B1-B2-H5. Helices 3 and 4 comprise the helix-turn-helix motif and the β-sheet is called the wing as in other wHTH, such as the dtxR-type or the merR-type. Helix 4 is termed the recognition helix, like in other HTHs where it binds the DNA major groove. Most ArsR/SmtB-like metalloregulators form homodimers . The dimer interface is formed by helix 5 and an N-terminal part . Two distinct metal-binding sites have been identified. The first site comprises cysteine thiolates located in the HTH in helix 3 and for some cases in the N terminus, called the alpha3(N) site . The second metal-binding site is located in helix 5 (and C terminus) and is called the α5(C) site. The alpha3N site binds large thiophilic, toxic metals including Cd, Pb, and Bi, as in S. aureus cadC. ArsR lacks the N-terminal arm and its α3 site coordinates smaller thiophilic ions like As and Sb. The α5 site contains carboxylate and imidazole ligands and interacts preferentially with biologically required metal ions including Zn, Co, and Ni. ArsR-type metalloregulators contain one of these sites, both, or other potential metal-binding sites . Binding of metal ions to these sites leads to allosteric changes that can derepress the operator/promoter DNA. The metal-inducible operons contain one or two imperfect 12-2-12 inverted repeats, which can be recognised by multimeric ArsR-type metalloregulators.

Some proteins known to contain an ArsR-type HTH domain:

Escherichia coli ArsR, an arsenic-responsive transcription repressor of the arsenic resistance operon (ars) which encodes an arsenate reductase and metal exporters.

Synechococcus PCC 7942 SmtB, a Zn(II)-responsive transcription repressor of the smtA gene that codes for a metallothionein. SmtB senses Co(II) and Cd(II) too, but Zn(II) is the preferred effector.

Staphylococcus aureus CadC, a transcription regulator of the cadmium resistance (cad) operon which encodes a Cd/Pb-specific efflux ATPase .

Mycobacterium tuberculosis CmtR, a Pb(II)/Cd(II)-sensing repressor .
von Willebrand factor, type D domain (VWF_type-D)
Type: Domain

Von Willebrand factor (VWF) is a large, multimeric blood glycoprotein synthesized in endothelial cells and megakaryocytes, that is required for normal hemostasis. Mutant forms are involved in the most common inherited bleeding disorder (von Willebrand disease: VWD). VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. It is also essential for the transport of the blood clotting factor VIII .

VWF is a large multidomain protein. The type D domain (VWFD) is not only required for blood clotting factor VIII binding but also for normal multimerization of VWF . The interaction between blood clotting factor VIII and VWF is necessary for normal survival of blood clotting factor VIII in blood circulation. The VWFD domain is a highly structured region, in which the first conserved Cys has been found to form a disulfide bridge with the second conserved one .

The VWFD domain can occur in association with a lot of different domains like vitellogenin, VWFC, VWFA, and ZP.

Proteins with a VWFD domain are listed below:

Mammalian von Willebrand factor (VWF), a multifunctional protein involved in maintaining homeostasis. It consists of 4 VWFD domains (D1-4), 3 VWFA domains, 3 VWFB domains, 2 VWFC domains, an X domain and a C-terminal cystine knot . There might be a third VWFC domain within the type B domain region . The structure of the VWF D3 domain has been revealed .

Mammalian zonadhesin, which binds in a species-specific manner to the zona pellucida of the egg.

Mammalian bone morphogenetic protein-binding (BMP-binding) endothelial regulator protein.

Mammalian alpha-tectorin, which is one of the major non-collagenous components of the tectorial membrane.

Mammalian mucins, glycoproteins that are major constituents of the glycocalyx that covers mucosal epithelium.

Mammalian vitellogenin, a major lipoprotein in many oviparous animals, which is a precursor of a lipid-binding product named as lipovitellin.

This entry represents the VWFD domain.
Peptidase S21 (Peptidase_S21)
Type: Family

This group of serine peptidases belong to MEROPS peptidase family S21 (assemblin family, clan 21). Assemblin is a serine protease with a unique fold and an active site that comprises the unusual triad Ser-His-His. It is found in herpesviruses, one of the groups of DNA viruses. Assemblin is involved in the late stages of assembly of the viral prohead, breaking down the scaffold protein upon which the prohead is assembled. In Epstein-Barr virus (EBV), a member of the Gammaherpesvirus family, it is also known as the maturational protease (BVRF2) . The structure of assemblin has been revealed . The dimerization of assemblin may induce allosteric changes that activate this protease .

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .
Non-structural protein NS3, peptidase S7, flavivirus (Flavi_NS3_S7)
Type: Domain

The viral genome of Flavivirus is a positive strand RNA that encodes a single polyprotein precursor. Processing of the polyprotein precursor into mature proteins is carried out by the host signal peptidase and by NS3 serine protease, which requires NS2B (

) as a cofactor.

Pathogenic members of the flavivirus family, including West Nile Virus (WNV) and Dengue Virus (DV), are growing global threats for which there are no specific treatments. The genome encodes three structural proteins found in the mature virion (C, prM, and E) and seven "nonstructural" (i.e., not part of the virion architecture) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Full-length NS3 is a bifunctional protein. The N-terminal 175 residues comprise a chymotrypsin-like protease, while the C-terminal portion is a helicase. The NS2B protein, which is located in the
polypeptide precursor immediately upstream of the NS3 protease domain, functions as the cofactor for NS3 protease. A 35-48 residue central portion is required for protease activity in vitro, while N- and C-terminal flanking hydrophobic regions are predicted to anchor the NS2B-NS3 complex into the host endoplasmic reticulum membrane. The two component flaviviral enzyme NS2B-NS3 cleaves the viral polyprotein precursor within the host cell, a process that is required for viral replication . The NS3 protease forms the MEROPS peptidase family S7 (flavivirin family), clan PA.

The NS3 protease has a classical serine protease catalytic triad (His, Asp, and Ser). The enzymatic activity is enhanced by interacting with the
central 40 amino acid of NS2B which acts as an essential cofactor. The NS3 protease domain has an overall structure of two barrels made of six β-sheets each, with the active site located in the cleft between the barrels. The NS2B hydrophilic core cofactor contributes one of the N-terminal β-sheets .
ABC transporter, permease (ABC_transp_permease)
Type: Family

ABC transporter is a large family mainly comprising high-affinity branched-chain amino acid transporter proteins such as Escherichia coli LivH (

) and LivM (

), both of which are from the LIV-I transport system . Also found with in this family are proteins from the galactose, ribose, xylose, arabinose and fructose transport system permeases , as well as nucleoside transporters .
Pyridoxal 5'-phosphate synthase subunit PdxS/SNZ (PdxS/SNZ)
Type: Family

The family of pyridoxal 5'-phosphate synthase subunits, known as the PdxS/SNZ family, occur in organisms in four kingdoms and form one of the most highly conserved families . A PdxS/SNZ protein has a classic (β/α)8-barrel fold, consisting of eight parallel β-strands alternating with eight α helices. PdxS subunits form two hexameric rings . Proteins are involved in vitamin B6 biosynthesis.

The term vitamin B6 is used to refer collectively to the compound pyridoxine and its vitameric forms, pyridoxal, pyridoxamine, and their phosphorylated derivatives. Vitamin B6 is required by all organisms and plays an essential role as a co-factor for enzymatic reactions. Plants, fungi, bacteria, archaebacteria, and protists synthetize vitamin B6. Animals and some highly specialised obligate pathogens obtain it nutritionally. Vitamin B6 has two distinct biosynthetic pathways, which do not coexist in any organism. The pdxA/pdxJ pathway, that has been extensively characterised in Escherichia coli, is found in the gamma subdivision of the proteobacteria. A second pathway of vitamin B6 synthesis involving the pdxS/SNZ and pdxT/SNO protein families, which are completely unrelated in sequence to the pdxA/pdxJ proteins, is found in plants, fungi, protists, archaebacteria and most bacteria .

PdxS/SNZ and pdxT/SNO proteins form a complex which serves as a glutamine amidotransferase to supply ammonia as a source of the ring nitrogen of vitamin B6 . PdxT/SNO and pdxS/SNZ appear to encode respectively the glutaminase subunit, which produces ammonia from glutamine, and the synthase subunit, which combines ammonia with five- and three-carbon phosphosugars to form vitamin B6 .
Large ribosomal subunit protein uL29 (Ribosomal_uL29)
Type: Family

This family includes ribosomal proteins, which constitute the uL29 family . These were previously known as L29 from eubacteria and archaea and L35 from eukaryotes.

Ribosomal protein uL29 is one of the proteins from the large ribosomal subunit. uL29 belongs to a family of ribosomal proteins of 63 to 138 amino-acid residues which, on the basis of sequence similarities, groups:

Red algal uL29.

Bacterial uL29.

Mammalian uL29 (known as L35)

Caenorhabditis elegans uL29 (known as L35) (ZK652.4).

Yeast uL29 (known as L35).

uL29 is located on the surface of the large ribosomal subunit, where it participates in forming a protein ring that surrounds the polypeptide exit channel, providing structural support for the ribosome . uL29 is involved in forming the translocon binding site, along with L19, L22, L23, L24, and L31e. In addition, uL29 and L23 form the interaction site for trigger factor (TF) on the ribosomal surface, adjacent to the exit tunnel . uL29 forms numerous interactions with L23 and with the 23S rRNA.

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 .
Beta-defensin-like domain (Defensin_beta-like)
Type: Domain

This entry represents a range of Beta defensins.

Defensins are 2-6kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses [

.

], containing three pairs of intramolecular disulphide bonds. On the basis of their size and pattern of disulphide bonding, mammalian defensins are classified into alpha, beta and theta categories. Every mammalian species explored thus far has beta-defensins. In cows, as many as 13 beta-defensins exist in neutrophils. However, in other species, beta-defensins are more often produced by epithelial cells lining various organs (e.g. the epidermis, bronchial tree and genitourinary tract).

Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins (CS) because they inhibit corticotropin-stimulated corticosteroid production. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form `channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesised as propeptides which may be relevant to this process.

Human, rabbit and guinea-pig beta-defensins, as well as human beta-defensin-2 (hBD2), induce the activation and degranulation of mast cells, resulting in the release of histamine and prostaglandin D2.
Somatostatin receptor 3 (Somatstn_rcpt_3)
Type: Family

Somatostatin (SST), also known as somatotropin release-inhibiting factor (SRIF), is a hypothalamic hormone, a pancreatic hormone, and a central and peripheral neurotransmitter. Somatostatin has a wide distribution throughout the central nervous system (CNS) as well as in peripheral tissues, for example in the pituitary, pancreas and stomach. The various actions of somatostatin are mediated by a family of rhodopsin-like G protein-coupled receptors, which comprise of five distinct subtypes: Somatostatin receptor 1 (SSTR1), Somatostatin receptor 2 (SSTR2), Somatostatin receptor 3 (SSTR3), Somatostatin receptor 4 (SSTR4) and Somatostatin receptor 5 (SSTR5) . These subtypes are widely expressed in many tissues , and frequently multiple subtypes coexist in the same cell . The somatostatin receptor subtypes also share common signalling pathways, such as the inhibition of adenylyl cyclase , activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K+ channels (SSTR2, SSTR3, SSTR4, SSTR5) , to voltage-dependent Ca2+ channels (SSTR1, SSTR2) , to an Na+/H+ exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, SSTR2), phospholipase C (SSTR2, SSTR5), and phospholipase A2 (SSTR4) .

This entry represents SSTR3. It is widely distributed in mouse brain, with high levels in the forebrain, hippocampus and amygdala; moderate levels are also present in the substantia nigra. All five human somatostatin receptors expressed in COS-7 cells are coupled to activation of phosphoinositide (PI)-specific PLC-beta; and Ca2+ mobilisation via pertussis toxin-sensitive G protein(s) with an order of potency of SSTR5 >SSTR2 >SSTR3 >SSTR4 >SSTR1 . Inhibition of angiogenesis has been shown to be via the SSTR3, and involves the inhibition of MAPK and endothelial nitric oxide synthase (eNOS) activity .
Large ribosomal subunit protein bL19 (Ribosomal_bL19)
Type: Family

This family represents the large ribosomal subunit protein bL19 found in bacteria and eukaryotes (which includes bL19c from plants (chloroplast), mitochondrial bL19m from animals, also referred to as MRLP19) . In Escherichia coli, bL19 is known to be located at the 30S-50S ribosomal subunit interface and may play a role in the structure and function of the aminoacyl-tRNA binding site.

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 .
Phosphatidylethanolamine-binding, conserved site (Phosphatidylethanolamine-bd_CS)
Type: Conserved_site

This entry groups metazoan phosphatidylethanolamine-binding proteins, carboxypeptidase Y inhibitor from Saccharomyces cerevisiae (Baker's yeast) (

), and homologues from plants which function in flower development. The members of this family belong to MEROPS proteinase inhibitor family I51, clan I-.
Large ribosomal subunit protein P1/P2, eukaryotes (Ribosomal_P1/P2_euk)
Type: Family

This entry represents a family of eukaryotic ribosomal proteins P1/P2.

Eukaryotic ribosomal P proteins have been classified according to their similarity to the mammalian P0, P1 and P2 proteins , all of which share a similar primary structure: an apparently globular N-terminal domain (which includes the protein core); an Ala-rich hinge region; and a highly-acidic Glu/Asp-rich C-terminal domain - this contains the ribosomal P consensus sequence EESDDDMGFGLFD, which protrudes from the ribosomal stalk.

The C-terminal regions of Trypanosoma cruzi P proteins are strongly immunogenic in Chagas disease. All 3 forms of the protein show the ability to generate autoimmune responses, but their antigenic properties differ as a result of discrepancies in their C-terminal sequences . The main linear epitope of the T. cruzi P1 and P2 proteins has been mapped to the 13-residue C-terminal sequence (R-13) EEEDDDMGFGLFD. This is identical to the eukaryotic P consensus, but has Ser substituted by Glu, yielding a more hydrophilic sequence, which is critical in determining the immunological reactivity of the T. cruzi R-13 epitope in Chagas disease.
Glycoside hydrolase, family 34 (Glyco_hydro_34)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 34

comprises enzymes with only one known activity; sialidase or neuraminidase

.

Neuraminidases cleave the terminal sialic acid residues from carbohydrate chains in glycoproteins. Sialic acid is a negatively charged sugar associated with the protein and lipid portions of lipoproteins. In Influenza virus, neuraminidases prevent self-aggregation by removing the carbohydrate from the viral envelope thus facilitating the mobility of the virus to and from the site of infection.
Antiviral agents that inhibit influenza viral neuraminidase activity are of major importance in the control of influenza .
Membrane attack complex component/perforin/complement C9 (MAC_perforin)
Type: Family

Complement component C9 is a multi-domain protein that contains an N-terminal type-1 TSP domain, an LDL-receptor class A repeat, a number of potential transmembrane (TM) regions and a C-terminal EGF-like domain . Hydropathy analysis of the sequence indicates the N-terminal half of C9 to be predominantly hydrophilic in character, while the C-terminal section is more hydrophobic. The amphipathic organisation of the primary structure is consistent with the known potential of polymerised C9 to penetrate lipid bilayers, causing the formation of transmembrane channels