SII-SWORD/CoKE huggingface dataset:
Iodothyronine deiodinase, active site (Iodothyronine_deiodinase_AS)
Type: Active_site

Iodothyronine deiodinase (

) (DI) is the vertebrate enzyme responsible for the deiodination of the prohormone thyroxine (T4 or 3,5,3',5'-tetraiodothyronine) into the biologically active hormone T3 (3,5,3'-triiodothyronine) and of T3 into the inactive metabolite T2 (3,3'-diiodothyronine). All known DI are proteins of about 250 residues that contain a selenocysteine at their active site. Three types of DI are known, type II is essential for providing the brain with the appropriate levels of T3 during the critical period of development, and type III is essential for the regulation of thyroid hormone inactivation during embryological development.

This signature found in the central part of the enzyme, which contains the active site selenocysteine.
Glycoside hydrolase, family 16, active site (GH16_AS)
Type: Active_site

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.

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.
Beta-glucanase (Beta_glucanase)
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.

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.
Lipase, GDSL, active site (Lipase_GDSL_AS)
Type: Active_site

A variety of lipolytic enzymes with serine as part of the active site have been identified . Protein sequences which contain this active site signature include; Aeromonas hydrophila lipase, Vibrio mimicus arylesterase, Vibrio parahaemolyticus thermolabile haemolysin, rabbit phospholipase (AdRab-B), and Brassica napus anther-specific proline-rich protein. A serine has been identified as part of the active site in the A. hydrophila, V. mimicus and Escherichia coli enzymes.
Tyrosine-protein kinase, active site (Tyr_kinase_AS)
Type: Active_site

This entry represents the tyrosine protein kinase active site. It also matches a number of proteins belonging to the atypical serine/threonine protein kinase BUD32 family, which lack the conventional structural elements necessary for the substrate recognition and also lack the lysine residue that in all other serine/threonine kinases participates in the catalytic event.

Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups :

Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis . RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction .

Cytoplasmic/non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases .

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 .
Peptidase S16, active site (Peptidase_S16_AS)
Type: Active_site

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) .

This signature defines the active site of the serine peptidases belonging to the MEROPS peptidase family S16 (lon protease family, clan SF). These proteases which are dependent on the hydrolysis of ATP for their activity and have a serine in their active site, they include:

Bacterial ATP-dependent proteases . The prototype of those bacterial enzymes is the Escherichia coli La protease (

) (gene lon). La is capable of hydrolysing large proteins; it degrades short-lived regulatory (such as rcsA and sulA) and abnormal proteins. It is a cytoplasmic protein of 87kDa that associates as an homotetramer. Its proteolytic activity is stimulated by single-stranded DNA.

Eukaryotic mitochondrial matrix proteases . The prototype of these enzymes is the yeast PIM1 protease. It is a mitochondrial matrix protein of 120kDa that associated as an homohexamer. It catalyses the initial step of mitochondrial protein degradation.

Haemophilus influenzae lon-B (HI1324), a protein which does not contain the ATP-binding domain, but possess a slightly divergent form of the catalytic domain.
Peptidase S16, Lon proteolytic domain (Lon_proteolytic)
Type: Domain

Lon (also known as endopeptidase La) is a multi-domain ATP- dependent protease found throughout all kingdoms of life. It is involved in protein quality control and several regulatory processes. All Lon proteases contain an ATPase domain belonging to the AAA+ superfamily of molecular machines, and a proteolytic domain with a serine-lysine catalytic dyad in which a lysine assists the catalytic serine in proteolytic cleavage. Lon proteases can be divided into two subfamilies: A type (A-Lons), which have a large multi-lobed N-terminal domain together with the ATPase and protease domains, and B type (B-Lons), which lack an N domain, but have a membrane-anchoring region emerging from the ATPase domain. B-Lons are found in Archaea, in which they are the lone membrane-anchored ATP-dependent protease. The soluble A-Lons are found in all bacteria and in eukaryotic cell organelles, such as mitochondria and peroxisomes, and are needed for recovery from various stress conditions . The Lon proteolytic domain forms peptidase family S16 of clan SJ .

The structure of the Lon proteolytic domain consists of six α helices and ten β strands .
Glycosyl hydrolases family 25, active site (Glyco_hydro_25_AS)
Type: Active_site

It has been shown that a number of cell-wall lytic enzymes (EC 3.2.1.17) are evolutionary related and can be classified into a single family:

Lysozymes (lysin) from Streptococcus pneumoniae bacteriophages of the Cp family.

Lysozyme (endolysin) from Lactococcus delbrueckii phage mv1.

Autolytic lysozyme from Clostridium acetobutylicum.

Lysozyme M1 from Streptomyces globisporus.

N,O-diacetylmuramidase (lysozyme ch) from the fungus Chalaropsis.

These proteins belong to the Chalaropsis (Ch)-type lyzozymes or glycosyl hydrolases family 25 (GH25) [E1]. The Ch-type lysozymes family GH25 exhibits both beta-1,4-N-acetylmuramidase and beta-1,4-N,6-O-diacetylmuramidase activities and its evolutionary spread is diverse, comprising bacterial, viral (mainly phage) and eukaryotic representatives.

The Ch-type lysozyme domain is structurally unrelated to the other lysozyme folds. It has a β/α-barrel fold and is composed of eight β-strands and six α-helices, with the strands forming the staves of the barrel and the helices located around it. A conserved active-site DxE motif may be implicated in catalysis, which could proceed through an oxazoline intermediate. The aspartate residue has been proposed to be the catalytic acid/base, initially protonating the leaving group to facilitate its departure (general acid assistance) and subsequently acting as a general base to activate the hydrolytic water molecule. The glutamate residue acts to stabilize or deprotonate the oxazoline N atom . A third residue, Asp6 of the profile, could also be involved in catalysis with the Glu of the DxE motif if the hydrolysis occurs via a net inversion of the anomeric configuration, with Asp6 acting as the general base, helping to activate the nucleophilic water molecule, and the Glu of the DxE motif acting as the general acid, protonating the departing oxygen atom in a concerted fashion as the bond cleaves .

Two residues, an aspartate and a glutamate, as well as some others in their vicinity are conserved in all proteins from this family.
Serine/threonine-protein kinase, active site (Ser/Thr_kinase_AS)
Type: Active_site

Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. In the central part of the catalytic domain there is a conserved aspartic acid residue, which is important for the catalytic activity of the enzyme .

This entry represents a conserved region that surrounds the active site aspartate residue and it is more specific for serine/threonine protein kinases. It also matches several dual-specificity protein kinases and members of WEE kinase family that are bona fide tyrosine protein kinases.

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 .
4-hydroxybenzoyl-CoA thioesterase, active site (HB-CoA_thioesterase_AS)
Type: Active_site

4-hydroxybenzoyl-CoA thioesterase (

) is an enzyme from Pseudomonas CBS-3, a soil-dwelling microbe that survives on 4-chlorobenzoate as its sole carbon source. This enzyme catalyses the last of the three steps in the pathway from 4-chlorobenzoate to hydroxybenzoate, the cleavage of the thioester bond of 4-hydroxybenzoyl-CoA to form hydroxybenzoate.

4-hydroxybenzoyl-CoA + H
2
O = 4-hydroxybenzoate + CoA

4-hydroxybenzoyl-CoA thioesterase is a protein of 141 amino-acid residues that assemble as an homotetramer. An aspartate in the N-terminal domain is thought to participate in the catalytic mechanism. This enzyme is evolutionary related to a number of uncharacterised proteins.

This signature spans the sequence which contains the active site aspartate residue.
Aldehyde oxidase/xanthine dehydrogenase, first molybdopterin binding domain (AldOxase/xan_DH_MoCoBD1)
Type: Domain

The aldehyde oxido-reductase (Mop) from the sulphate reducing anaerobic Gram-negative bacterium Desulfovibrio gigas is a homodimer of 907 amino acid residues subunits and is a member of the xanthine oxidase family. The protein contains a molybdopterin cofactor (Mo-co) and two different [2Fe-2S] centres. It is folded into four domains of which the first two bind the iron sulphur centres and the last two are involved in Mo-co binding. Mo-co is a molybdenum molybdopterin cytosine dinucleotide. Molybdopterin forms a tricyclic system with the pterin bicycle annealed to a pyran ring. The molybdopterin dinucleotide is deeply buried in the protein. The cis-dithiolene group of the pyran ring binds the molybdenum, which is coordinated by three more (oxygen) ligands .

This domain represents the first molybdopterin cofactor (Mo-Co) binding domain.

Aldehyde oxidase (AOX

) catalyses the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide. The enzyme is a homodimer, and requires FAD, molybdenum and two 2FE-2S clusters as cofactors. Xanthine dehydrogenase (XDH

) catalyses the hydrogenation of xanthine to urate, and also requires FAD, molybdenum and two 2FE-2S clusters as cofactors. This activity is often found in a bifunctional enzyme with xanthine oxidase (

) activity too. The enzyme can be converted from the dehydrogenase form to the oxidase form irreversibly by proteolysis or reversibly through oxidation of sulfhydryl groups .
Acyl-CoA dehydratase activase domain (CoA_E_activase_dom)
Type: Domain

This domain is found in a set of closely related prokaryotic [4Fe-4S]-containing ATPases, including activators of (R)-2-hydroxyglutaryl-CoA dehydratase, (R)-phenyllactate dehydratase, lactoyl-CoA dehydratase, and benzoyl-CoA reductase, as well as the uncharacterised protein YjiL of E. coli. Characterised members of this family provide a key reactive electron that their cognate enzyme requires for activity, and can use for multiple reaction cycles until the electron is lost and needs to be replaced .
Concentrative nucleoside transporter (C_nuclsd_transpt)
Type: Family

Nucleosides are hydrophilic molecules and require specialised transport proteins for permeation of cell membranes. There are two types of nucleoside transport processes: equilibrative bidirectional processes driven by chemical gradients, and inwardly directed concentrative processes driven by an electrochemical gradient . The two types of nucleoside transporters are classified into two families: the solute carrier (SLC) 29 and SLC28 families, corresponding to equilibrative and concentrative nucleoside transporters, respectively .

The microbial proteins include broad specificity transporters, such as the Escherichia coli NupC protein which transports all nucleosides (both ribo- and deoxyribonucleosides) except hypoxanthine and guanine nucleosides . Bacillus subtilis NupC transporter has been shown to be involved in transport of the pyrimidine nucleoside uridine . A recently characterised fungal protein, the first transporter of this type to be described in eukaryotes, exhibited transport activity for adenosine, uridine, inosine and guanosine but not cytidine, thymidine or the nucleobase hypoxanthine .

The characterised mammalian proteins can be divided into three subgroups; CNT1, CNT2 and CNT3 . CNT1 preferentially transports pyrimidines and weakly transports adenosine. Several antiviral and anticancer nucleoside analogues, including AZT and dFdC are also substrates for CNT1. CNT2 selectively transports purines, and the human form has also been shown to facilitate the uptake of some antiviral compounds including ddI and ribavirin. CNT3 has a broader specificity, transporting both purines and pyrimidines. Several anticancer nucleoside analogues such as CdA, dFdC and FdU are also transported by CNT3. Substrate specificity appears to depend on a region containing transmembrane regions 7, 8 and 9. Mutation of just four residues in this region was sufficient to convert the activity of human CNT1 to that of CNT2. At least three other concentrative nucleoside transport activities have been described in mammalian cells, but the proteins responsible for these activities have not yet been identified.

This entry represents a family of Concentrative Nucleoside Transporter (CNT) proteins found in bacteria and eukaryotes. Most of the bacteria and fungi homologues identified are H+ symporters, while the mammalian members (CNT1/2/3) are mostly Na+ symporters. However, mammalian CNT3 exhibits uniquely broad cation interactions with Na+, H+, and Li+ and can couple transport of uridine to uptake of H(+) .
4'-phosphopantetheinyl transferase domain (4-PPantetheinyl_Trfase_dom)
Type: Domain

The 4'-phosphopantetheinyl transferase superfamily of proteins transfer the 4'-phosphopantetheine (4'-PP) moiety from coenzyme A (CoA) to the invariant serine of pp-binding. This post-translational modification renders holo-ACP capable of acyl group activation via thioesterification of the cysteamine thiol of 4'-PP . This superfamily consists of two subtypes: The ACPS type such as ACPS_ECOLI and the Sfp type such as SFP_BACSU. The structure of the Sfp type is known , which shows the active site accommodates a magnesium ion. The most highly conserved regions of the alignment are involved in binding the magnesium ion.
PEP-utilising enzyme, mobile domain (PEP-util_enz_mobile_dom)
Type: Domain

A number of enzymes that catalyse the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) via a phospho-histidine intermediate have been shown to be structurally related . All these enzymes share the same catalytic mechanism: they bind PEP and transfer the phosphoryl group from it to a histidine residue. This domain is a "swivelling" β/β/α domain which is thought to be mobile in all proteins known to contain it . It is often found associated with the pyruvate phosphate dikinase, PEP/pyruvate-binding domain (

) at its N terminus.
Tubulin/FtsZ, C-terminal (Tub_FtsZ_C)
Type: Homologous_superfamily

This domain superfamily is found in the tubulin alpha, beta and gamma chains, as well as the bacterial FtsZ family of proteins. These proteins are GTPases and are involved in polymer formation. Tubulin is the major component of microtubules, while FtsZ is the polymer-forming protein of bacterial cell division, it is part of a ring in the middle of the dividing cell that is required for constriction of cell membrane and cell envelope to yield two daughter cells. FtsZ can polymerise into tubes, sheets, and rings
in vitro
and is ubiquitous in bacteria and archaea. This is the C-terminal domain.
Peptidase M17, leucyl aminopeptidase, N-terminal (Peptidase_M17_N)
Type: Domain

This group of metallopeptidases belong to the MEROPS peptidase family M17 (leucyl aminopeptidase family, clan MF), the type example being leucyl aminopeptidase from Bos taurus (Bovine).

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 .