SII-SWORD/CoKE huggingface dataset:
Thymidine/pyrimidine-nucleoside phosphorylase (Thymidine/pyrmidine_PPase)
Type: Family

Two highly similar activities are represented in this group: thymidine phosphorylase (TP, gene deoA,

) and pyrimidine-nucleoside phosphorylase (PyNP, gene pdp,

). Both are dimeric enzymes that function in the salvage pathway to catalyse the reversible phosphorolysis of pyrimidine nucleosides to the free base and sugar moieties. In the case of thymidine phosphorylase, thymidine (and to a lesser extent, 2'-deoxyuridine) is lysed to produce thymine (or uracil) and 2'-deoxyribose-1-phosphate. Pyrimidine-nucleoside phosphorylase performs the analogous reaction on thymidine (to produce the same products) and uridine (to produce uracil and ribose-1-phosphate). PyNP is typically the only pyrimidine nucleoside phosphorylase encoded by Gram-positive bacteria, while eukaryotes and proteobacteria encode two: TP, and the unrelated uridine phosphorylase. In humans, TP was originally characterised as platelet-derived endothelial cell growth factor and gliostatin . Structurally, the enzymes are homodimers, each composed of a rigid all α-helix lobe and a mixed α-helix/β-sheet lobe, which are connected by a flexible hinge . Prior to substrate binding, the lobes are separated by a large cleft. A functional active site and subsequent catalysis occurs upon closing of the cleft. The active site, composed of a phosphate binding site and a (deoxy)ribonucleotide binding site within the cleft region, is highly conserved between the two enzymes of this group. Active site residues (Escherichia coli DeoA numbering) include the phosphate binding Lys84 and Ser86 (close to a glycine-rich loop), Ser113, and Thr123, and the pyrimidine nucleoside-binding Arg171, Ser186, and Lys190. Sequence comparison between the active site residues for both enzymes reveals only one difference , which has been proposed to partially mediate substrate specificity. In TP, position 111 is a methionine, while the analogous position in PyNP is lysine. It should be noted that the uncharacterised archaeal members of this family differ in a number of respects from either of the characterised activities. The residue at position 108 is lysine, indicating the activity might be PyNP-like (though the determinants of substrate specificity have not been fully elucidated). Position 171 is glutamate (negative charge side chain) rather than arginine (positive charge side chain). In addition, a large loop that may "lock in" the substrates within the active site is much smaller than in the characterised members. It is not clear what effect these and other differences have on activity and specificity.
Large ribosomal subunit protein eL31 (Ribosomal_eL31)
Type: Family

A number of eukaryotic and archaebacterial large subunit ribosomal proteins can be grouped on the basis of sequence similarities. These proteins have 87 to 128 amino-acid residues. This family consists of:

Yeast eL31A (also known as L34)

Archaeal L31

Plants L31

Mammalian L31

Ribosomal protein eL31, which is present in archaea and eukaryotes, binds the 23S rRNA and is one of six protein components encircling the polypeptide exit tunnel. It is a component of the eukaryotic 60S (large) ribosomal subunit, and the archaeal 50S (large) ribosomal subunit .

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 .
Type I restriction modification DNA specificity domain (Restrct_endonuc_typeI_TRD)
Type: Domain

This domain is also known as the target recognition domain (TRD). Restriction-modification (R-M) systems protect a bacterial cell against invasion of foreign DNA by endonucleolytic cleavage of DNA that lacks a site specific modification. The host genome is protected from cleavage by methylation of specific nucleotides in the target sites. In type I systems, both restriction and modification activities are present in one heteromeric enzyme complex composed of one DNA specificity subunit (this entry), two modification (M) subunits and two restriction (R) subunits .
Ribulose-phosphate 3-epimerase-like (Ribul_P_3_epim-like)
Type: Family

Ribulose-phosphate 3-epimerase (

) (also known as RPE, pentose-5-phosphate 3-epimerase or PPE) is the enzyme that converts D-ribulose 5-phosphate (Ru5P) into D-xylulose 5-phosphate in Calvin's reductive pentose phosphate cycle. In Ralstonia eutropha (Alcaligenes eutrophus) two copies of the gene coding for PPE are known , one is chromosomally encoded

, the other one is on a plasmid

. PPE has been found in a wide range of bacteria, archaebacteria, fungi and plants. All the proteins have from 209 to 241 amino acid residues. The enzyme has a TIM barrel structure.

This family also includes other enzymes from the ribulose-phosphate 3-epimerase family, like D-allulose-6-phosphate 3-epimerase and other putative pentose-5-phosphate 3-epimerases. D-allulose-6-phosphate 3-epimerase catalyses the reversible epimerization of D-allulose 6-phosphate to D-fructose 6-phosphate, but it can also catalyse with lower efficiency the reversible epimerization of D-ribulose 5-phosphate to D-xylulose 5-phosphate .
CXC chemokine receptor 2 (Chemokine_CXCR2)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.

CXCR1 and CXCR2, also known as interleukin 8 receptor alpha and beta, respectively , are closely-related receptors. They act as specific receptors for the CXCL8 and CXCL6 chemokines, which have a glutamate-leucine-arginine (ELR) motif in their N-terminal domains . CXCR2 also binds additional ELR motif-containing CXC chemokines (such as
CXCL1, CXCL2, CXCL3, CXCL5 and CXCL7) with high affinity .

CXCR1 and CXCR2 are expressed on all granulocytes, monocytes, and mast cells and on some CD8+ T-cells and CD56+ natural killer (NK) cells . Equal amounts of CXCR1 and CXCR2 are present on neutrophils , but it appears that monocytes and positive lymphocytes express more CXCR2 than CXCR1 .

This entry represents CXCR2. The angiogenic effects of CXCL8 in intestinal microvascular endothelial cells are mediated by this receptor . It has been suggested that the receptor may be a potential theraputic target in acute lung injury .
Zinc finger, AN1-type (Znf_AN1)
Type: Domain

This entry represents the AN1-type zinc finger domain, which has a dimetal (zinc)-bound α/β fold. This domain was first identified as a zinc finger at the C terminus of AN1

, a ubiquitin-like protein in Xenopus laevis . The AN1-type zinc finger contains six conserved cysteines and two histidines that could potentially coordinate 2 zinc atoms.

Certain stress-associated proteins (SAP) contain AN1 domain, often in combination with A20 zinc finger domains (SAP8) or C2H2 domains (SAP16) . For example, the human protein Znf216 has an A20 zinc-finger at the N terminus and an AN1 zinc-finger at the C terminus, acting to negatively regulate the NFkappaB activation pathway and to interact with components of the immune response like RIP, IKKgamma and TRAF6. The interact of Znf216 with IKK-gamma and RIP is mediated by the A20 zinc-finger domain, while its interaction with TRAF6 is mediated by the AN1 zinc-finger domain; therefore, both zinc-finger domains are involved in regulating the immune response . The AN1 zinc finger domain is also found in proteins containing a ubiquitin-like domain, which are involved in the ubiquitination pathway . Proteins containing an AN1-type zinc finger include:

Ascidian posterior end mark 6 (pem-6) protein .

Human AWP1 protein (associated with PRK1), which is expressed during early embryogenesis .

Human immunoglobulin mu binding protein 2 (SMUBP-2), mutations in which cause muscular atrophy with respiratory distress type 1 .

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
NUDIX hydrolase, NudL, conserved site (NUDIX_hydrolase_NudL_CS)
Type: Conserved_site

Nudix hydrolases, which are commonly found in all kingdoms of life, are pyrophosphohydrolases predominantly acting on substrates that contain a nucleotide diphosphate linked to another moiety X . These substrates include nucleoside triphosphates, nucleotide sugars, dinucleoside polyphosphates, dinucleotide coenzymes and capped RNAs. In some cases, phosphohydrolase activity has been observed with nucleoside diphopshates and some non-nucletoide substrates. These enzymes posses an almost universally conserved, charateristic twenty-three-amino acid motif, Gx(5)Ex(5)[UA]xREx(2)EExGU (where U is an aliphatic, hydrophobic amino acid residue), necessary for catalytic activity. Some members of this family protect cells by degrading potentially mutagenic oxidised nucleotides, while others control the levels of metabolic intermediates and signalling compounds.

This entry represents a number of proteins which contain the characteristic Nudix domain. One of the characterised protein in this entry, PCD1, is a peroxisomal coenzyme A (CoA) diphosphatase catalysing the cleavage of coenzyme A into ADP and phosphopantetheine, with a strong preference for oxidised CoA disulphide as its substrate . PCD1 may function, therefore, to maintain the capacity for beta-oxidation of fatty acids. It has also been shown to degrade oxo-dGTP and so may also be involved in protecting the cell from mutagenic oxidised nucleotides .
BCCT transporter family (BCCT_transptr)
Type: Family

These prokaryotic transport proteins belong to a family known as BCCT (for Betaine/Carnitine/Choline Transporters) and are specific for compounds containing a quaternary nitrogen atom. The BCCT proteins contain 12 transmembrane regions and are energised by proton symport. They contain a conserved region with four tryptophans in their central region .
SWAP/Surp (Surp)
Type: Domain

SWAP is derived from the Suppressor-of-White-APricot splicing regulator from Drosophila melanogaster. The domain is found in regulators responsible for pervasive, nonsex-specific alternative pre-mRNA splicing characteristics and has been found in splicing regulatory proteins . These ancient, conserved SWAP proteins share a colinearly arrayed series of novel sequence motifs .
Leptin (Leptin)
Type: Family

Leptin, a metabolic monitor of food intake and energy need, is expressed by the ob obesity gene. The protein may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot , the hormone effectively turning the brain's appetite message off when it senses that the body is satiated. Obese humans have high levels of the protein, suggesting a similarity to type II (adult onset) diabetes, in which sufferers over-produce insulin, but can't respond to it metabolically - they have become insulin resistant. Similarly, it is thought that obese individuals may be leptin resistant.
Antenna complex, alpha/beta subunit (Antenna_a/b)
Type: Domain

The antenna complexes of photosynthetic bacteria function as light-harvesting systems that absorb light and transfer the excitation energy to the reaction centres. The antenna complexes usually comprise 2 polypeptides (alpha- and beta-chains), 2-3 bacteriochlorophyll molecules and some carotenoids .
The alpha- and beta-chains are small proteins of 40-70 residues. Each has an N-terminal hydrophilic cytoplasmic domain, a single transmembrane (TM) region, and a small C-terminal hydrophilic periplasmic domain. In both chains, the TM domain houses a conserved His residue, presumed to be involved in binding the magnesium atom of a bacteriochlorophyll group. The beta-chains are characterised by a further histidine at the C-terminal extremity of the cytoplasmic domain, which is also thought to be involved in bacteriochlorophyll binding.
Flagellar M-ring protein FliF (FlgMring_FliF)
Type: Family

This family corresponds to the FliF protein. FliF is the major protein of the M-ring in bacterial flagellar basal body . The basal body consists of four rings (L,P,S and M) surrounding the flagellar rod, which is believed to transmit motor rotation to the filament . The M ring is integral to the inner membrane of the cell, and may be connected to the rod via the S (supramembrane) ring, which lies just distal to it. The L and P rings reside in the outer membrane and periplasmic space, respectively. FliF lacks a signal peptide and is predicted to have considerable α-helical structure, including an N-terminal sequence that is likely to be membrane-spanning . Overall, however, FliF has a relatively hydrophilic sequence, with a high charge density, especially towards its C terminus .
GPCR, family 3, extracellular calcium-sensing receptor-related (GPCR_3_Ca_sens_rcpt-rel)
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 metabotropic glutamate receptors are functionally and pharmacologically distinct from the ionotropic glutamate receptors. They are coupled to G-proteins and stimulate the inositol phosphate/Ca
2+
intracellular signalling pathway . At least eight sub-types of metabotropic receptor (GRM1-8) have been identified in cloning studies. The sub-types differ in their agonist pharmacology and signal transduction pathways.

The calcium-sensing receptor (CaSR) is an integral membrane protein that senses changes in the extracellular concentration of calcium ions. The activity of the receptor is mediated by a G-protein that activates a phosphatidyl-inositol-calcium second messenger system. The sequences of the receptors show a high degree of similarity to the TM signature that characterises the metabotropic glutamate receptors. In addition, the sequences contain a large extracellular domain that includes clusters of acidic amino acid residues, which may be involved in calcium binding . Defects in CaSR that result in reduced activity of the receptor cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), inherited conditions characterised by altered calcium homeostasis . FHH-affected individuals exhibit mild or modest hypercalcemia, relative hypocalciuria and inappropriately normal PTH levels. By contrast, NSHPT is a rare autosomal recessive life-threatening disorder characterised by high serum calcium concentrations, skeletal demineralisation and parathyroid hyperplasia. In addition, defects resulting from receptor activation at subnormal Ca
2+
levels cause autosomal dominant hypocalcemia .

This entry represents the extracellular calcium-sensing receptors and related proteins in GPCR family 3, such as the taste receptors.
Envelope glycoprotein M, flavivirus (Env_glycoprot_M_flavivir)
Type: Domain

Flaviviruses are small enveloped viruses with virions comprised of three proteins called C, M and E . The envelope glycoprotein M is made as a precursor, called prM. The precursor portion of the protein is the signal peptide for the proteins entry into the membrane. prM is cleaved to form M in a late-stage cleavage event. Associated with this cleavage is a change in the infectivity and fusion activity of the virus.
Pectinesterase, catalytic (Pectinesterase_cat)
Type: Domain

Pectinesterase

(pectin methylesterase) catalyses the de-esterification of pectin into pectate and methanol. Pectin is one of the main components of the plant cell wall. In plants, pectinesterase plays an important role in cell wall metabolism during fruit ripening. In plant bacterial pathogens such as Erwinia carotovora and in fungal pathogens such as Aspergillus niger, pectinesterase is involved in maceration and soft-rotting of plant tissue. Plant pectinesterases are regulated by pectinesterase inhibitors, which are ineffective against microbial enzymes .

Prokaryotic and eukaryotic pectinesterases share a few regions of sequence similarity. The crystal structure of pectinesterase from Erwinia chrysanthemi revealed a β-helix structure similar to that found in pectinolytic enzymes, though it is different from most structures of esterases . The putative catalytic residues are in a similar location to those of the active site and substrate-binding cleft of pectate lyase.
Immunodeficiency lentiviral matrix, N-terminal (Lentvrl_matrix_N)
Type: Domain

Retroviral matrix proteins (or major core proteins) are components of envelope-associated capsids, which line the inner surface of virus envelopes and are associated with viral membranes . Matrix proteins are produced as part of Gag precursor polyproteins. During viral maturation, the Gag polyprotein is cleaved into major structural proteins by the viral protease, yielding the matrix (MA), capsid (CA), nucleocapsid (NC), and some smaller peptides. Gag-derived proteins govern the entire assembly and release of the virus particles, with matrix proteins playing key roles in Gag stability, capsid assembly, transport and budding. Although matrix proteins from different retroviruses appear to perform similar functions and can have similar structural folds which predominantly consist of four closely packed α-helices that are interconnected through loops, their primary sequences can be very different .

This entry represents matrix proteins from immunodeficiency lentiviruses, such as Human immunodeficiency virus (HIV) and Simian immunodeficiency virus (SIV-cpz) . The structure of the HIV protein consists of 5 α helices, a short 3.10 helix and a 3-stranded mixed β-sheet .