SII-SWORD/CoKE huggingface dataset:
Alanine racemase (Ala_racemase)
Type: Family

Alanine racemase catalyses the pyridoxal-dependent conversion of L-alanine into D-alanine, a key component of bacterial peptidoglycan . In Escherichia coli and Salmonella typhimurium, there are two alanine racemase isoforms, alr is a biosynthetic form required for cell wall formation; and dadB functions in L-alanine catabolism. By contrast with dadB and alr, both of which are monomeric enzymes, the alanine racemase of Bacillaceae are homodimers. In Pseudomonas putida, a broad-specificity amino acid racemase is structurally and functionally related to alanine racemase. The 3D-structure of the dimeric alanine racemase from Bacillus stearothermophilus has been determined to a resolution of 1.9 A . Each monomer comprises two domains, with an eight-stranded α/β barrel at the N terminus, and a C-terminal β-strand domain. In the dimer, the mouth of the α/β barrel of one monomer faces the second domain of the other monomer. The pyridoxal 5'-phosphate (PLP) cofactor lies in and above the barrel mouth and is covalently linked via an aldimine linkage to Lys39. Several other residues are involved in anchoring the PLP, for example, Arg219 forms a hydrogen bond with the pyridine nitrogen of the cofactor, which is assumed to influence electron delocalisation in PLP-alanine intermediates; Arg136 donates a hydrogen bond to the phenolic oxygen of PLP, and may be involved in substrate binding and stabilisation of intermediates; and Tyr265' is postulated to be a 2 proton donor to the carbanion intermediate .

A particular case is represented by Enterococcus VanT, which has both serine and alanine racemase activities, although it is able to racemize serine more efficiently than alanine. Unlike other alanine and serine racemases, VanT is a transmembrane protein. At least ten transmembrane helices are predicted to be present in the N-terminal domain and the C-terminal domain has structural homology with the alanine racemase and it is matched by this entry.
Plant peroxidase (Peroxidase_pln)
Type: Family

Peroxidases are haem-containing enzymes that use hydrogen peroxide as the electron acceptor to catalyse a number of oxidative reactions. Most haem peroxidases follow the reaction scheme:

Fe
3+
+ H
2
O
2
-->[Fe
4+
=O]R' (Compound I) + H
2
O

[Fe
4+
=O]R' + substrate -->[Fe
4+
=O]R (Compound II) + oxidised substrate

[Fe
4+
=O]R + substrate -->Fe
3+
+ H
2
O + oxidised substrate

In this mechanism, the enzyme reacts with one equivalent of H
2
O
2
to give [Fe
4+
=O]R' (compound I). This is a two-electron oxidation/reduction reaction where H
2
O
2
is reduced to water and the enzyme is oxidised. One oxidising equivalent resides on iron, giving the oxyferryl intermediate, while in many peroxidases the porphyrin (R) is oxidised to the porphyrin pi-cation radical (R'). Compound I then oxidises an organic substrate to give a substrate radical .

Peroxidases are found in bacteria, fungi, plants and animals and can be viewed as members of a superfamily consisting of 3 major classes. Class III comprises the secretory plant peroxidases, which have multiple tissue-specific functions e.g., removal of hydrogen peroxide from chloroplasts and cytosol; oxidation of toxic compounds; biosynthesis of the cell wall; defence responses towards wounding; indole-3-acetic acid (IAA) catabolism; ethylene biosynthesis; and so on. The wide spectrum of peroxidase activity, coupled with the participation in various physiological processes, is in keeping with its relative lack of specificity for substrates and the occurrence of a variety of isozymes. Plant peroxidases are monomeric glycoproteins containing 4 conserved disulphide bridges and 2 calcium ions. The 3D structure of peanut peroxidase has been shown to possess the same helical fold as class I and II peroxidases .
Transcription attenuation protein MtrB (MtrB)
Type: Family

This entry represents transcription attenuation protein MtrB. MtrB is required for transcription attenuation control in the Trp operon. This trans-acting factor seems to recognise a 10 bases nucleotide sequence in the Trp leader transcript causing transcription termination. It binds the leader RNA only in presence of L-tryptophan .
SUF system FeS cluster assembly, SufBD core domain (SUF_FeS_clus_asmbl_SufBD_core)
Type: Domain

This entry represents the core domain of SufB and SufD proteins, which are homologous, and form part of the SufBCD complex in the SUF system . SufB accepts sulfur transferred from SufE , whereas SufD may play a role in iron acquisition . This domain adopts a right-handed β-helix fold .

Iron-sulphur (FeS) clusters are important cofactors for numerous proteins involved in electron transfer, in redox and non-redox catalysis, in gene regulation, and as sensors of oxygen and iron. These functions depend on the various FeS cluster prosthetic groups, the most common being [2Fe-2S] and [4Fe-4S] . FeS cluster assembly is a complex process involving the mobilisation of Fe and S atoms from storage sources, their assembly into [Fe-S] form, their transport to specific cellular locations, and their transfer to recipient apoproteins. So far, three FeS assembly machineries have been identified, which are capable of synthesising all types of [Fe-S] clusters: ISC (iron-sulphur cluster), SUF (sulphur assimilation), and NIF (nitrogen fixation) systems.

The SUF system is an alternative pathway to the ISC system that operates under iron starvation and oxidative stress. It is found in eubacteria, archaea and eukaryotes (plastids). The SUF system is encoded by the suf operon (sufABCDSE), and the six encoded proteins are arranged into two complexes (SufSE and SufBCD) and one protein (SufA). SufS is a pyridoxal-phosphate (PLP) protein displaying cysteine desulphurase activity. SufE acts as a scaffold protein that accepts S from SufS and donates it to SufA . SufC is an ATPase with an unorthodox ATP-binding cassette (ABC)-like component. SufA is homologous to IscA , acting as a scaffold protein in which Fe and S atoms are assembled into [FeS] cluster forms, which can then easily be transferred to apoproteins targets.
Formyl peptide receptor-related (Formyl_rcpt-rel)
Type: Family

Formyl peptide receptors (FPR) are members of the rhodopsin-like G-protein coupled receptor family and are involved in chemotaxis . They were originally identified by their ability to bind N-formyl peptides (typified by fMet-Leu-Phe (fMLP)), produced by the degradation of either bacterial or host cells but subsequent ligands have been discovered, containing many microbial agonists derived from both bacteria and viruses .

FPRs were initially found on leukocytes, but they are expressed in other cells, for example, immature dendritic cells, platelets, microglial cells, astrocytes, fibroblasts and platelets . FPRs are expressed at high levels on polymorphonuclear and mononuclear phagocytes. Formyl peptide receptors are not only involved in mediating immune cell response to infection, but also act to suppress the immune system under certain conditions . The main responses elicited upon ligation of formylated peptides, are those of morphological polarization, locomotion, production of reactive-oxygen species and release of proteolytic enzymes . There are three formyl peptide receptor subtypes, FPR1, FPR2 and FPR3 . The sequence similarity between FPR1 and FPR2 is high (69%), and although there is a large sequence similarity also between FPR2 and FPR3 (83%), FPR3 can not bind formylated peptides .

This entry includes the formyl peptide receptors and other related receptors such as C3a and C5a anaphylatoxin chemotactic receptors and G-protein-coupled receptor CMKlR1 .
CC chemokine, conserved site (Chemokine_CC_CS)
Type: Conserved_site

Many low-molecular weight factors secreted by cells including fibroblasts, macrophages and endothelial cells, in response to a variety of stimuli such as growth factors, interferons, viral transformation and bacterial products, are structurally related . Most members of this family of proteins seem to have mitogenic, chemotactic or inflammatory activities. These small cytokines are also called intercrines or chemokines. They are cationic proteins of 70 to 100 amino acid residues that share four conserved cysteine residues involved in two disulphide bonds. These proteins can be sorted into two groups based on the spacing of the two amino-terminal cysteines. In the first group, the two cysteines are separated by a single residue (C-x-C), while in the second group, they are adjacent (C-C). The 'C-C' group is currently known to include monocyte chemotactic proteins 1 (MCP-1), 2 (MCP-2), 3 and 4; macrophage inflammatory protein 1 alpha (MIP-1-alpha), beta (MIP-1-beta) and gamma (MIP-1-gamma); macrophage inflammatory protein 3 alpha and beta, 4 and 5; LD78 beta; SIS-epsilon (p500); thymus and activation-regulated chemokine (TARC); Eotaxin; I-309; human proteins HCC-1/NCC-2 and HCC-3; and mouse protein C10.
Monellin, A chain (Monellin_A)
Type: Family

Monellin is an intensely sweet-tasting protein derived from African berries. The protein has a very high specificity for the sweet receptors, making it ~100,000 times sweeter than sugar on a molar basis and several thousand times sweeter on a weight basis. Like the sweet-tasting protein thaumatin, it neither contains carbohydrates nor modified amino acids. Although there is no sequence similarity between the proteins, antibodies for thaumatin compete for monellin (and other sweet compounds, but not for chemically modified non-sweet monellin) and vice versa . It is thought that native conformations are important for the sweet taste. Monellin is a heterodimer, comprising an A chain of 44 amino acid residues, and a B chain of 50 residues. The individual subunits are not sweet, nor do they block the sweet sensation of sucrose or monellin. However, blocking the single SH of monellin abolishes its sweetness, as does reaction of its methionyl residue with CNBr . The cysteinyl and methionyl residues are adjacent, and it has therefore been suggested that this part of the molecule is essential for its sweetness . The structure of monellin belongs to the α/β class, a 5-stranded β-sheet sequestering a single α-helix. The A chain contributes 3 strands to the sheet.
DAGK family (DAGK)
Type: Family

Prokaryotic diacylglycerol kinase (DAGK) and undecaprenol kinase (UDPK) constitute a family of multispan membrane enzymes that are very small, lack relationships to any other family of proteins and exhibit an unusual structure. Escherichia coli DAGK plays an important role in recycling diacylglycerol produced as a by-product of biosynthesis of molecules located in the periplasmic space. UDPK seems to play an analogous role in Gram-positive bacteria, where it is essential for biofilm formation by the oral pathogen Streptococcus mutans . In Bacillus subtilis, UDPK is an essential kinase in the diacylglycerol cycle involved in lipoteichoic acid production and seems to be indispensable for the maintenance of spore stability and viability .

Diacylglycerol kinase (

) (DAGK) is an enzyme that catalyses the formation of phosphatidic acid from diacylglycerol and ATP, an important step in phospholipid biosynthesis. In bacteria DAGK is a very small (13 to 15 kD) membrane protein which seems to contain three transmembrane domains .
Peripherin/rom-1 (Peripherin/rom-1)
Type: Family

The outer segments of vertebrate rod photoreceptor cells are specialised organelles that function in the transduction of light into electrical signals as part of the visual excitation process. These organelles contain thousands of closely-stacked disk membranes, which have distinctly different protein compositions in their lamellar and rim regions . Peripherin (or RDS) and rom-1 are related retinal-specific memebers of the tetraspanin family which are located at the rims of the photoreceptor disks, where they may act jointly in disk morphogenesis . Both peripherin and rom-1 form disulphide-linked homodimers. Defects in the peripherin gene (RDS) cause various human diseases such as autosomal dominant retinitis pigmentosa, autosomal dominant punctata albescens and butterfly-shaped pigment dystrophy. In mice it causes retinopathy known as 'retinal degeneration slow' (rds). These proteins contain about 350 amino acid residues. Structurally they consist of a short cytoplasmic N-terminal domain, followed by four transmembrane segments that delimit two lumenal and one cytoplasmic loops; the C-terminal domain is cytoplasmic. The second lumenal loop is very large (about 140 amino acid residues) and contains seven conserved cysteines.
Trp repressor (Trp_repress)
Type: Family

The Trp repressor (TrpR) binds to at least five operators in the Escherichia coli genome, repressing gene expression. The operators at which it binds vary considerably in DNA sequence and location within the promoter; when bound to the Trp operon it recognises the sequence 5'-ACTAGT-3' and acts to prevent the initiation of transcription. The TrpR controls the trpEDCBA (trpO) operon and the genes for trpR, aroH, mtr and aroL, which are involved in the biosynthesis and uptake of the amino acid tryptophan . The repressor binds to the operators only in the presence of L-tryptophan, thereby controlling the intracellular level of its effector; the complex also regulates Trp repressor biosynthesis by binding to its own regulatory region. TrpR acts as a dimer that is composed of identical 6-helical subunits, where four of the helices form the core of the protein and intertwine with the corresponding helices from the other subunit.
GPCR, family 2, secretin-like (GPCR_2_secretin-like)
Type: Family

This entry represents G-protein coupled receptor 2 family.

The secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

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 .
Alpha-amylase inhibitor (A-amylase_inhib)
Type: Family

Alpha-amylase inhibitor inhibits mammalian alpha-amylases specifically, by forming a tight stoichiometric 1:1 complex with alpha-amylase. The inhibitor has no action on plant and microbial alpha amylases.

A crystal structure has been determined for tendamistat, the 74-amino acid inhibitor produced by Streptomyces tendae that targets a wide range of mammalian alpha-amylases . The binding of tendamistat to alpha-amylase leads to the steric blockage of the active site of the enzyme. The crystal structure of tendamistat revealed an immunoglobulin-like fold that could potentially adopt multiple conformations. Such molecular flexibility could enable an induced-fit type of binding that would both optimise binding and allow broad target specificity.
Peptidase M14, carboxypeptidase A (Peptidase_M14)
Type: Domain

This group of sequences contain a diverse range of gene families, which include metallopeptidases belonging to MEROPS peptidase family M14 (carboxypeptidase A, clan MC), subfamilies M14A and M14B.

The carboxypeptidase A family can be divided into four subfamilies: M14A (carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) . Members of subfamily M14B have longer C-terminal than those of subfamily M14A , and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble .

ATP/GTP binding protein (AGTPBP-1/Nna1)-like proteins are active metallopeptidases that act on cytosolic proteins such as alpha-tubulin to remove a C-terminal tyrosine. Mutations in AGTPBP-1/Nna1 cause Purkinje cell degeneration (pcd). AGTPBP-1/Nna1-like proteins from the different phyla are highly diverse, but they all contain a unique N-terminal conserved domain right before the CP domain. It has been suggested that this N-terminal domain might act as a folding domain .

The zinc ligands have been determined as two histidines and a glutamate, and the catalytic residue has been identified as a C-terminal glutamate, but these do not form the characteristic metalloprotease HEXXH motif . Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts .

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .
MarR-type HTH domain (HTH_MarR-typ)
Type: Domain

The MarR-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain of about 135 amino acids present in transcription regulators of the MarR/SlyA family, involved in the development of antibiotic resistance. The MarR family of transcription regulators is named after Escherichia coli MarR, a repressor of genes which activate the multiple antibiotic resistance and oxidative stress regulons, and after slyA from Salmonella typhimurium and E. coli, a transcription regulator that is required for virulence and survival in the macrophage environment. Regulators with the MarR-type HTH domain are present in bacteria and archaea and control a variety of biological functions, including resistance to multiple antibiotics, household disinfectants, organic solvents, oxidative stress agents and regulation of the virulence factor synthesis in pathogens of humans and plants. Many of the MarR-like regulators respond to aromatic compounds .

The crystal structures of MarR, MexR and SlyA have been determined and show a winged HTH DNA-binding core flanked by helices involved in dimerisation. The DNA-binding domains are ascribed to the superfamily of winged helix proteins, containing a three (four)-helix (H) bundle and a three-stranded antiparallel β-sheet (B) in the topology: H1-(H1')-H2-B1-H3-H4-B2-B3-H5-H6. Helices 3 and 4 comprise the helix-turn-helix motif and the β-sheet is called the wing. Helix 4 is termed the recognition helix, like in other HTHs where it binds the DNA major groove. The helices 1, 5 and 6 are involved in dimerisation, as most MarR-like transcription regulators form dimers .
Phosphoribosyltransferase domain (PRTase_dom)
Type: Domain

This entry refers to the phosphoribosyl transferase (PRT) type I domain. PRTases catalyze the displacement of the alpha-1'-pyrophosphate of 5-phosphoribosyl-alpha1-pyrpphosphate (PRPP) by a nitrogen-containing nucleophile. The reaction products are an alpha-1 substituted ribose-5'-phosphate and a free pyrophosphate (PP). PRPP, an activated form of ribose-5-phosphate, is a key metabolite connecting nucleotide synthesis and salvage pathways. The type I PRTases are identified by a conserved PRPP binding motif which features two adjacent acidic residues surrounded by one or more hydrophobic residue. This domain is found in a range of diverse phosphoribosyl transferase enzymes and regulatory proteins of the nucleotide synthesis and salvage pathways, including adenine phosphoribosyltransferase

, hypoxanthine-guanine-xanthine phosphoribosyltransferase, hypoxanthine phosphoribosyltransferase

, ribose-phosphate pyrophosphokinase

, amidophosphoribosyltransferase

, orotate phosphoribosyltransferase

, uracil phosphoribosyltransferase

, and xanthine-guanine phosphoribosyltransferase

. In Arabidopsis, at the very N terminus of this domain is the P-Loop NTPase domain .
AP-1 transcription factor (AP-1)
Type: Family

The transcription factor activator protein (AP)-1 consists of Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF and JDP family members . They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes . This entry includes Fos, ATF-3 and JDP family members.

AP-1 proteins have an α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif . They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') . Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions .