SII-SWORD/CoKE huggingface dataset:
Small ribosomal subunit protein uS9 (Ribosomal_uS9)
Type: Family

uS9 proteins adopt a β/α/β fold similar to that found in numerous RNA/DNA-binding proteins, as well as in kinases from the GHMP kinase family .

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 .
D-alanyl-D-alanine dipeptidase (A_A_dipeptidase)
Type: Family

This group of metallopeptidases belong to MEROPS peptidase family M15 (clan MD), subfamily M15D (vanX D-Ala-D-Ala dipeptidase).

The D-alanyl-D-alanine dipeptidase enzyme from Enterococcus faecalis is also known as the vancomycin resistance protein VanX, and hydrolyses D-ala-D-ala. It has a 250-fold differential in catalytic efficiency for hydrolysis of D-ala-D-ala versus D-ala-D-lactate. The latter therefore remains intact for subsequent incorporation into peptidoglycan precursors that terminate in the dipeptide D-ala-D-lactate rather than the dipeptide D-ala-D-ala, thereby preventing vancomycin from binding. The enzyme requires a metal cofactor, and is induced by vancomycin through regulation by VanS and VanR.
Diacylglycerol kinase, accessory domain (Diacylglycerol_kin_accessory)
Type: Domain

Diacylglycerol (DAG) is a second messenger that acts as a protein kinase C activator. The DAG kinase domain is assumed to be an accessory domain. Upon cell stimulation, DAG kinase converts DAG into phosphatidate, initiating the resynthesis of phosphatidylinositols and attenuating protein kinase C activity. It catalyses the reaction: ATP + 1,2-diacylglycerol = ADP +
1,2-diacylglycerol 3-phosphate. The enzyme is stimulated by calcium and phosphatidylserine and phosphorylated by protein kinase C. This domain is always associated with

.

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
Beta-glucanase-like, N-terminal domain (Beta-glucanase-like)
Type: Domain

This entry represents the N-terminal domain in members of the glycoside hydrolase family 16 (GH16), including Beta-glucanase, Crh-like protein 1, Xyloglucan endotransglucosylase/hydrolase and related proteins.

The glycosyl hydrolases family 16 (GH16) contains functionally heterogeneous members, including lichenase (

); xyloglucan xyloglucosyltransferase (

); agarase (

); kappa-carrageenase (

); endo-beta-1,3-glucanase (

); endo-beta-1,3-1,4-glucanase (

); endo-beta-galactosidase (

). These enzymes share a common ancestor and have diverged significantly in their primary sequence.

The GH16 catalytic domain has a classical sandwich-like β-jelly roll fold, formed by two main, closely packed and curved antiparallel β-sheets, creating a deep channel harboring the catalytic machinery. Even though the GH16 domains have now diverged significantly in their primary sequences, they all feature a common catalytic motif, E-[ILV]-D-[IVAF]-[VILMF](0,1)-E. The two glutamic acid residues in the conserved motif are the nucleophile and the general base involved in catalysis, whereas the aspartic acid residue is important in maintaining the relative position of these catalytic amino acids .

Two closely clustered conserved glutamates have been shown to be involved in the catalytic activity of Bacillus licheniformis lichenase. This domain contains these residues.
Virulence-related outer membrane protein (Enterovir_OMP)
Type: Family

Virulence-related outer membrane proteins are expressed in Gram-negative bacteria and are essential to bacterial survival within macrophages and for eukaryotic cell invasion. Members of this group include:

PagC, required by Salmonella typhimurium for survival in macrophages and for virulence in mice

Rck outer membrane protein of the S. typhimurium virulence plasmid

Ail, a product of the Yersinia enterocolitica chromosome capable of mediating bacterial adherence to and invasion of epithelial cell lines

OmpX from Escherichia coli that promotes adhesion to and entry into mammalian cells. It also has a role in the resistance against attack by the human complement system

a Bacteriophage lambda outer membrane protein, Lom

The crystal structure of OmpX from E. coli reveals that OmpX consists of an eight-stranded antiparallel all-next-neighbour β barrel . The structure shows two girdles of aromatic amino acid residues and a ribbon of nonpolar residues that attach to the membrane interior. The core of the barrel consists of an extended hydrogen-bonding network of highly conserved residues. OmpX thus resembles an inverse micelle. The OmpX structure shows that the membrane-spanning part of the protein is much better conserved than the extracellular loops. Moreover, these loops form a protruding β sheet, the edge of which presumably binds to external proteins. It is suggested that this type of binding promotes cell adhesion and invasion and helps defend against the complement system. Although OmpX has the same β-sheet topology as the structurally related outer membrane protein A (OmpA)

, their barrels differ with respect to the shear numbers and internal hydrogen-bonding networks.
Inositol monophosphatase-like (Inositol_monophosphatase-like)
Type: Family

It has been shown that several proteins share two sequence motifs . Two of these proteins, vertebrate and plant inositol monophosphatase (

), and vertebrate inositol polyphosphate 1-phosphatase (

), are enzymes of the inositol phosphate second messenger signalling pathway, and share similar enzyme activity. Both enzymes exhibit an absolute requirement for metal ions (Mg2 is preferred), and their amino acid sequences contain a number of conserved motifs, which are also shared by several other proteins related to MPTASE (including products of fungal QaX and qutG, bacterial suhB and cysQ, and yeast hal2) . The function of the other proteins is not yet clear, but it is suggested that they may act by enhancing the synthesis or degradation of phosphorylated messenger molecules .

Structural analysis of these proteins has revealed a common core of 155 residues, which includes residues essential for metal binding and catalysis. An interesting property of the enzymes of this family is their sensitivity to Li+. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of manic depression .
Melanocyte-stimulating hormone receptor (MSH_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 .

Melanocyte-stimulating hormones (MSH), adrenocorticotrophin (ACTH) and beta-endorphin are peptide products of pituitary pro-opiomelanocortin. MSH has a trophic action on melanocytes, and regulates pigment production in fish and amphibia. The MSH receptor is expressed in high levels in melanocytes, melanomas and their derived cell lines. Receptors are found in low levels in the CNS. MSH regulates temperature control in the septal region of the brain and releases prolactin from the pituitary.
Midkine heparin-binding growth factor (Midkine_heparin-bd_GF)
Type: Family

Several extracellular heparin-binding proteins involved in regulation of growth and differentiation belong to a new family of growth factors. These growth factors are highly related proteins of about 140 amino acids that contain 10 conserved cysteines probably involved in disulphide bonds, and include pleiotrophin (also known as heparin-binding growth-associated molecule HB-GAM, heparin-binding growth factor 8 HBGF-8, heparin-binding neutrophic factor HBNF and osteoblast specific protein OSF-1); midkine (MK) ; retinoic acid-induced heparin-binding protein (RIHB) ; and pleiotrophic factors alpha-1 and -2 and beta-1 and -2 from Xenopus laevis, the homologues of midkine and pleiotrophin respectively. Pleiotrophin is a heparin-binding protein that has neurotrophic activity and has mitogenic activity towards fibroblasts. It is highly expressed in brain and uterus tissues, but is also found in gut, muscle and skin. It is thought to possess an important brain-specific function. Midkine is a regulator of differentiation whose expression is regulated by retinoic acid, and, like pleiotrophin, is a heparin-binding growth/differentiation factor that acts on fibroblasts and nerve cells.
Catalase-peroxidase haem (Catalase_peroxidase)
Type: Family

Haem-containing catalase-peroxidases are bifunctional antioxidant enzymes that exhibit both catalase (

) and peroxidase (

) activity, and which are present predominantly in bacterial species . Several evolutionary lineages are present also in archaeal, fungal, and protistan species. These enzymes provide protection against oxidative stress by dismutating hydrogen peroxide to oxygen and water . Phylogenetically they are closely related to ascorbate peroxidases and cytochrome c peroxidases and can be divided in two distinct clades . They do not share sequence similarity with mono-functional, haem-containing catalases (

) that are ubiquitous in aerobic organisms, nor with non-haem manganese-containing catalases found in bacteria (

). Catalases perform a unique two-step reaction cycle that cleaves two hydrogen peroxide molecules heterolytically to alternately oxidise and reduce the haem iron thus releasing water and molecular oxygen . Contrary, peroxidases use hydrogen peroxide only to oxidise the haem iron, but use different electron donors such as NADH or ascorbate to then reduce the haem.

The structure of the catalase-peroxidase from the archaeon, Haloarcula marismortui (Halobacterium marismortui), reveals a dimer of two identical subunits , although some catalase-peroxidases can exist also as homotetramers. The general topology, as well as the arrangement of the catalytic residues and haem in the active site, are similar to other class I peroxidases. However, the location of the haem group deeply buried inside the domain is typical of a catalase. The primary structure of the subunit can be divided into two similar halves, which very probably arose from a gene duplication event . A similar structure was obtained also for a catalase-peroxidase from the proteobacterium Burkholderia pseudomallei .
Uridine kinase-like (Uridine_kinase-like)
Type: Family

This entry represents the uridine kinase like proteins.
Galactose-1-phosphate uridyl transferase, class II (GalP_uridyl_Trfase_II)
Type: Family

Galactose-1-phosphate uridyl transferase

(GalT) catalyses the transfer of an uridyldiphosphate group on galactose (or glucose) 1-phosphate. During the reaction, the uridyl moiety links to a histidine residue. In the Escherichia coli enzyme, it has been shown that two histidine residues separated by a single proline residue are essential for enzyme activity.

On the basis of sequence similarities, two apparently unrelated families seem to exist. Class-I enzymes are found in eukaryotes as well as some bacteria such as E. coli or Streptomyces lividans, while class-II enzymes have been found so far only in bacteria such as Bacillus subtilis or Lactobacillus helveticus .
NAD:arginine ADP-ribosyltransferase, ART (ART)
Type: Family

Mono-ADP-ribosylation is a post-translational modification of proteins in which the ADP-ribose moiety of NAD is transferred to proteins. This process is responsible for the toxicity of some bacterial toxins (e.g., cholera and pertussis toxins). Mono (ADP-ribosyl) transferases exist in vertebrates

that transfer ADP-ribose to arginine .

NAD
+
+ L-arginine = nicotinamide + N2-(ADP-D-ribosyl)-L-arginine

At least five forms of the enzyme have been characterised to date, some of which are attached to the membrane via glycosylphosphatidylinositol (GPI) anchors, while others appear to be secreted. The enzymes contain ~250-300 residues, which encode putative signal sequences and carbohydrate attachment sites. In addition, the N- and C-termini are predominantly hydrophobic, a characteristic of GPI-anchored proteins .
Regulatory protein Rop (Regulatory_Rop)
Type: Family

The Rop protein regulates plasmid DNA replication by modulating the initiation of transcription of the primer RNA precursor. Processing of the precursor, RNAII, is inhibited by hydrogen bonding of RNAII to its complementary sequence in RNAI. Rop increases the affinity of RNAI for RNAII and thus decreases the rate of replication initiation events. The 3D structure of Rop has been determined by X-ray crystallography and refined to 1.7A resolution. The 63 amino acid protein is a homodimer, each monomer consisting almost entirely of two α-helices, the whole molecule forming a highly regular four-α-helix bundle . This can be approximated by a four-stranded rope, with radius 7.0 A, a left-handed helical twist, and pitch 172.5 A. A very compact packing of side chains in the helix interfaces of the Rop coiled-coil structure is presumed to account for its high stability . The overall details of the structure have been confirmed by proton NMR .
SAND domain (SAND_dom)
Type: Domain

The SAND domain (named after Sp100, AIRE-1, NucP41/75, DEAF-1) is a conserved ~80 residue region found in a number of nuclear proteins, many of which function in chromatin-dependent transcriptional control. These include proteins linked to various human diseases, such as the Sp100 (Speckled protein 100kDa) , NUDR (Nuclear DEAF-1 related), GMEB (Glucocorticoid Modulatory Element Binding) proteins and AIRE-1 (Autoimmune regulator 1) proteins.

Proteins containing the SAND domain have a modular structure; the SAND domain can be associated with a number of other modules, including the bromodomain, the PHD finger and the MYND finger. Because no SAND domain has been found in yeast, it is thought that the SAND domain could be restricted to animal phyla. Many SAND domain-containing proteins, including NUDR, DEAF-1 (Deformed epidermal autoregulatory factor-1) and GMEB, have been shown to bind DNA sequences specifically. The SAND domain has been proposed to mediate the DNA binding activity of these proteins .

The resolution of the 3D structure of the SAND domain from Sp100b has revealed that it consists of a novel α/β fold. The SAND domain adopts a compact fold consisting of a strongly twisted, five-stranded antiparallel β-sheet with four α-helices packing against one side of the β-sheet. The opposite side of the β-sheet is solvent exposed. The β-sheet and α-helical parts of the structure form two distinct regions. Multiple hydrophobic residues pack between these regions to form a structural core. A conserved KDWK sequence motif is found within the α-helical, positively charged surface patch. The DNA binding surface has been mapped to the α-helical region encompassing the KDWK motif .
Fructose-bisphosphate aldolase, class-II (FBA_II)
Type: Family

Class-II aldolases , mainly found in prokaryotes and fungi, are homodimeric enzymes, which require a divalent metal ion, generally zinc, for their activity. They include fructose-bisphosphate aldolase , a glycolytic enzyme that catalyses the reversible aldol cleavage or condensation of fructose-1,6-bisphosphate into dihydroxyacetone-phosphate and glyceraldehyde 3-phosphate. The family also includes the Escherichia coli galactitol operon protein, gatY, which catalyses the transformation of tagatose 1,6-bisphosphate into glycerone phosphate and D-glyceraldehyde 3-phosphate; and E. coli N-acetyl galactosamine operon protein, agaY, which catalyses the same reaction. There are two histidine residues in the first half of the sequence of these enzymes that have been shown to be involved in binding a zinc ion .
Ricin B, lectin domain (Ricin_B_lectin)
Type: Domain

Ricin is a legume lectin from the seeds of the castor bean plant, Ricinus communis. The seeds are poisonous to people, animals and insects and just one milligram of ricin can kill an adult.

Primary structure analysis has shown the presence of a similar domain in many carbohydrate-recognition proteins like plant and bacterial AB-toxins, glycosidases or proteases . This domain, known as the ricin B lectin domain, can be present in one or more copies and has been shown in some instance to bind simple sugars, such as galactose or lactose.

The ricin B lectin domain is composed of three homologous subdomains of 40 amino acids (alpha, beta and gamma) and a linker peptide of around 15 residues (lambda). It has been proposed that the ricin B lectin domain arose by gene triplication from a primitive 40 residue galactoside-binding peptide . The most characteristic, though not completely conserved, sequence feature is the presence of a Q-W pattern. Consequently, the ricin B lectin domain as also been refered as the (QxW)
3
domain and the three homologous regions as the QxW repeats . A disulphide bond is also conserved in some of the QxW repeats .

The 3D structure of the ricin B chain has shown that the three QxW repeats pack around a pseudo threefold axis that is stabilised by the lambda linker . The ricin B lectin domain has no major segments of a helix or β-sheet but each of the QxW repeats contains an ω-loop . An idealized ω-loop is a compact, contiguous segment of polypeptide that traces a 'loop-shaped' path in three-dimensional space; the main chain resembles a Greek omega.
Granulocyte-macrophage colony-stimulating factor (GM_colony-stim-fac)
Type: Family

Granulocyte-macrophage colony-stimulating factor (GMCSF) is a cytokine that acts in hematopoiesis to stimulate growth and differentiation of hematopoietic precursor cells from various lineages including granulocytes, macrophages, eosinophils and erythrocytes . GMCSF is a glycoprotein of ~120 residues that contains 4 conserved cysteines that participate in disulphide bond formation. The crystal structure of recombinant human GMCSF has been determined . There are two molecules in the asymmetric unit, which are related by an approximate non-crystallographic 2-fold axis. The overall structure, which is highly compact and globular with a predominantly hydrophobic core, is characterised by a 4-α-helix bundle. The helices are arranged in a left-handed anti-parallel fashion, with two overhand connections. Within the connections is a two-stranded anti-parallel β-sheet. The tertiary structure has a topology similar to that of Sus scrofa (pig) growth factor and interferon-beta. Most of the proposed critical regions for receptor binding are located on a continuous surface at one end of the molecule that includes the C terminus .
Peptidyl-prolyl cis-trans isomerase, FKBP-type, N-terminal (PPIase_FKBP_N)
Type: Domain

Peptidyl-prolyl cis-trans isomerase (PPIase) catalyses the cis-trans isomerisation of proline imidic peptide bonds in oligopeptides . This α helical domain is found at the N terminus of proteins belonging to the FKBP-type peptidyl-prolyl cis-trans isomerase family.

Peptidyl-prolyl cis-trans isomerase has been shown to accelerate the refolding of several proteins in vitro ; the FKPB-type enzymes probably act in the folding of extracytoplasmic proteins.