SII-SWORD/CoKE huggingface dataset:
Natriuretic peptide (Natr_peptide)
Type: Family

Atrial natriuretic peptides (ANPs) are vertebrate hormones that play an important role in the control of cardiovascular homeostatis, and sodium and water balance in general . There are different NPs that vary in length but share a common core. All are processed from a single precursor. A disulphide bond resident in the C-terminal section is required for full activity of atriopeptins. The family of NPs includes structurally-related peptides that elicit similar pharmacological spectra. Amongst these are brain natriuretic peptide (BNP); C-type natriuretic peptide (CNP); ventricular natriuretic peptide (VNP) ; and green mamba natriuretic peptide (DNP) .
Lethal(2) giant larvae protein (Lethal2_giant)
Type: Family

The lethal(2)giant larvae protein (Lgl) of Drosophila is essential for polarised epithelia development, for cell polarity associated with asymmetric cell division of neuroblasts during development and for oocyte polarity formation. As a result of alternative splicing Lgl has two isoforms that differ in their C-terminal region, isoform p78 which has an essential role in control of cell proliferation and differentiation during development as well as in controlling membrane trafficking underlying axonal growth and acts as a tumour suppressor ; and isoform p127 which has an accessory function in cell proliferation control and differentiation during development. These proteins, and their homologues, contain conserved functional domains such as homo-oligomerization domains, a cluster of phosphorylation sites and at least two WD-40 repeats, which suggests that these proteins have closely related functions .
Haemagglutinin/haemagglutinin-neuraminidase, paramyxovirus (Hemagglutn/HN)
Type: Family

This entry represents the haemagglutinin-neuraminidase (HN) glycoprotein found in a variety of paramyxoviruses (negative-stranded RNA viruses), including Mumps virus, Human parainfluenza virus 3, and the avian pathogen Newcastle disease virus. It also includes hemagglutinin glycoproteins from Morbiliviruses, a genus belonging to the Paramyxoviridae family that includes the Measles virus. Morbiliviruses hemagglutinins have no neuraminidase activity .

HN is a multi-functional protein with three distinct functions: a receptor-binding (haemagglutinin) activity, a receptor-destroying (neuraminidase) activity, and a membrane fusion activity that fuses the viral envelope to the host cell membrane in order to infect the cell.
Peptidase S13, D-Ala-D-Ala carboxypeptidase C (Peptidase_S13)
Type: Family

This family of serine peptidases belong to MEROPS peptidase family S13 (D-Ala-D-Ala carboxypeptidase C, clan SE). The active site residues occur in the motif SXXK.

D-Ala-D-Ala carboxypeptidase C is involved in the metabolism of cell components ; it is synthesised with a leader peptide to target it to the cell membrane . After cleavage of the leader peptide, the enzyme is retained in the membrane by a C-terminal anchor . There are three families of serine-type D-Ala-D-Ala peptidase (designated S11, S12 and S13), which are also known as low molecular weight penicillin-binding proteins . Family S13 comprises D-Ala-D-Ala peptidases that have sufficient sequence similarity around their active sites to assume a distant evolutionary relationship to other clan members; members of the S13 family also bind penicillin and have D-amino-peptidase activity. Proteases of family S11 have exclusive D-Ala-D-Ala peptidase activity, while some members of S12 are C beta-lactamases .

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) .
Mannitol dehydrogenase (Mannitol_DH)
Type: Family

Mannitol dehydrogenases catalyse the NAD-dependent reduction of mannitol-1-phosphates as part of the phosphoenolpyruvate-dependent phosphotransferase system (PTS). The PTS facilitates the vectorial translocation of metabolisable carbohydrates to form the corresponding sugar phosphates, which are then converted to glycolytic intermediates . Mannitol 2-dehydrogenase catalyses the NAD-dependent reduction of mannitol to fructose .
Several dehydrogenases have been shown to be evolutionary related, including mannitol-1-phosphate 5-dehydrogenase (

) (gene mtlD), mannitol 2-dehydrogenase (

) (gene mtlK); mannonate oxidoreductase (

) (fructuronate reductase) (gene uxuB); Escherichia coli hypothetical proteins ydfI and yeiQ; and yeast hypothetical protein YEL070w.
Urotensin II receptor (Urot_II_rcpt)
Type: Family

Urotensin II (UII) is a vasoactive somatostatin-like or cortistatin-like peptide hormone. However, despite the apparent structural similarity to these peptide hormones, they are not homologous to UII. Urotensin II was first identified in fish spinal cord but later found in humans and other mammals . In fish, UII is secreted at the back part of the spinal cord, in a neurosecretory centre called uroneurapophysa, and is involved in the regulation of the renal and cardiovascular systems . In mammals, urotensin II is the most potent mammalian vasoconstrictor identified to date and causes contraction of arterial blood vessels, including the thoracic aorta .

The urotensin II receptor is a rhodopsin-like G-protein coupled receptor, which binds urotensin-II . The receptor was previously known as GPR14, or sensory epithelial neuropeptide-like receptor (SENR) . The UII receptor is expressed in the CNS (cerebellum and spinal cord), skeletal muscle, pancreas, heart, endothelium and vascular smooth muscle . It is involved in the pathophysiological control of cardiovascular function and may also influence CNS and endocrine functions . Binding of urotensin II to the receptor leads to activation of phospholipase C, through coupling to Gq/11 family proteins. The resulting increase in intracellular calcium may cause the contraction of vascular smooth muscle .

This entry represents the urotensin II receptor.
Peptidase A31 family (Peptidase_A31)
Type: Family

This group represents metallopeptidases of the MEROPS peptidase family A31 (HybD endopeptidase family). Peptidase family A31 includes endopeptidases involved in hydrogenase maturation. HycI (hydrogenase 3 maturation protease) is a protease involved in the C-terminal processing of HycE, the large subunit of hydrogenase 3 . HybD is involved in processing of pre-HybC (the large subunit of hydrogenase 2) ; and HyaD is assumed to be involved in processing of the large subunit of hydrogenase 1.

The large subunit of [NiFe]-hydrogenase, as well as other nickel metalloenzymes, is synthesized as a precursor devoid of the metalloenzyme active site. This precursor undergoes a complex post-translational maturation process that requires a number of accessory proteins . At one step of this process, after nickel incorporation, each hydrogenase isoenzyme is processed by proteolytic cleavage at the C-terminal end by the corresponding hydrogenase maturation endopeptidase . The cleavage site is after a His or an Arg, liberating a short peptide . This cleavage occurs only in the presence of nickel, and the endopeptidase probably uses the metal in the large subunit of [NiFe]-hydrogenases as a recognition motif . There is no direct evidence for the active site or substrate-binding site, but there are predictions based on an available structure .

Nomenclature note: the following names are used in different organisms for members of this group: HycI, HybD, HyaD, HoxM, HoxW, HupD, HynC, HupM, VhoD, VhtD . Gene/protein names are sometimes used interchangeably to designate various "hydrogenase cluster" proteins unrelated to each other in various organisms. For example, the following names are used for members of this group, but also for unrelated proteins: HupD is used in Azotobacter chroococcum and Anabaena species to designate an unrelated hydrogenase maturation factor; HydD is used to designate hydrogenase structural genes in Thermococcus litoralis, Pyrococcus abyssi, and other species.
Tetrahydrofolate dehydrogenase/cyclohydrolase (THF_DH/CycHdrlase)
Type: Family

Enzymes that participate in the transfer of one-carbon units require the coenzyme tetrahydrofolate (THF). Various reactions generate one-carbon derivatives of THF, which can be interconverted between different oxidation states by methylene-THF dehydrogenase (

), methenyl-THF cyclohydrolase (

) and formyl-THF synthetase (

) . The dehydrogenase and cyclohydrolase activities are expressed by a variety of multifunctional enzymes, including the tri-functional eukaryotic C1-tetrahydrofolate synthase ; a bifunctional eukaryotic mitochondrial protein; and the bifunctional Escherichia coli folD protein . Methylene-tetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclo-hydrolase share an overlapping active site , and as such are usually located together in proteins, acting in tandem on the carbon-nitrogen bonds of substrates other than peptide bonds.
Signal transduction response regulator, chemotaxis, protein-glutamate methylesterase (Sig_transdc_resp-reg_Me-estase)
Type: Domain

This entry represents the signal transduction response regulator CheB involved in chemotaxis. CheB methylesterase is responsible for removing the methyl group from the gamma-glutamyl methyl ester residues in the methyl-accepting chemotaxis proteins (MCP). The enzyme catalyses the reaction: protein L-glutamate O-methyl ester and water is converted to protein L-glutamate and methanol. CheB
is regulated through phosphorylation by CheA. The N-terminal region of the protein is similar to that of other regulatory components of sensory transduction systems. The Myxococcus xanthus FrzG protein also belongs to this family, and is required for the normal aggregation of cells during fruiting body formation.

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .
Aldehyde oxidase/xanthine dehydrogenase, a/b hammerhead (Ald_Oxase/Xan_DH_a/b)
Type: Domain

Aldehyde oxidase (

) 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 (

) 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 sulphydryl groups.

The aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain is an evolutionary conserved protein domain .

This entry includes also the a/b hammerhead domain of the Nicotine 6-hydroxylase ndhL that is involved in the degradation of nicotine .
Cutinase/acetylxylan esterase (Cutinase/axe)
Type: Family

Plant pathogenic fungi produce extracellular degradative enzymes that play an important role in pathogenesis. They include cutinase, which hydrolyses cutin, facilitating fungus penetration through the cuticle. Cutinase is a serine esterase containing the classical Ser, His, Asp triad of serine hydrolases. The protein belongs to the α-β class, with a central β-sheet of 5 parallel strands covered by 5 helices on either side of the sheet. The active site cleft is partly covered by 2 thin bridges formed by amino acid side chains, by contrast with the hydrophobic lid possessed by other lipases . The protein also contains 2 disulphide bridges, which are essential for activity, their cleavage resulting in complete loss of enzymatic activity.

In the actinobacteria Kineococcus radiotolerans, this enzyme shows a C-terminal extension that is similar to the substrate binding domain of poly(hydroxybutyrate) (PHB) depolymerases .

Acetylxylan esterase from fungi removes acetyl side groups from xylan. The catalytic core of the enzyme has an α/β/α-sandwich fold, similar to that of cutinase .

This protein family also includes enzymes that do not show cutinase activity but exhibit esterase activity, such as phospholipases and carboxylesterases from Actinobacteria. Phospholipase Culp4 from Mycobacterium tuberculosis hydrolyses dipalmitoylphosphatidylcholine , while Carboxylesterase Culp1 from Mycobacterium tuberculosis hydrolyses various p-nitrophenol-linked aliphatic esters and has weak lipase activity .
Chitinase-like (Chitinase-like)
Type: Family

This entry includes Chitinase 1/2 from Tulipa saxatilis subsp. bakeri. They are class IIIb chitinases .
Zinc finger, GATA-type (Znf_GATA)
Type: Domain

This entry represents GATA-type zinc fingers (Znf). A number of transcription factors (including erythroid-specific transcription factor and nitrogen regulatory proteins), specifically bind the DNA sequence (A/T)GATA(A/G) in the regulatory regions of genes. They are consequently termed GATA-binding transcription factors. The interactions occur via highly-conserved Znf domains in which the zinc ion is coordinated by four cysteine residues . NMR studies have shown the core of the Znf to comprise two irregular anti-parallel β-sheets and an α-helix, followed by a long loop to the C-terminal end of the finger. The N-terminal part, which includes the helix, is similar in structure, but not sequence, to the N-terminal zinc module of the glucocorticoid receptor DNA-binding domain. The helix and the loop connecting the two β-sheets interact with the major groove of the DNA, while the C-terminal tail wraps around into the minor groove. It is this tail that is the essential determinant of specific binding. Interactions between the Znf and DNA are mainly hydrophobic, explaining the preponderance of thymines in the binding site; a large number of interactions with the phosphate backbone have also been observed . Two GATA zinc fingers are found in the GATA transcription factors. However there are several proteins which only contains a single copy of the domain.
Borrelia lipoprotein (Borrelia_lipo)
Type: Family

This family of lipoproteins is found in Borrelia spirochetes. They are known as variable large proteins (vlp). The function of these proteins is uncertain, but it may serve to avoid the host immune response by changing from one surface exposed variable major outer membrane lipoprotein to another .
Beta 3 adrenoceptor (ADRB3_rcpt)
Type: Family

The adrenoceptors (or adrenergic receptors) are rhodopsin-like G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity, and a variety of metabolic and central nervous system functions. The clinical uses of adrenergic compounds are vast. Agonists and antagonists interacting with adrenoceptors have proved useful in the treatment of a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy, and glaucoma. These drugs are also useful in several other therapeutic situations including shock, premature labour and opioid withdrawal, and as adjuncts to general anaesthetics.

There are three classes of adrenoceptors, based on their sequence similarity, receptor pharmacology and signalling mechanisms . These three classes are alpha 1 (a Gq coupled receptor), alpha 2 (a Gi coupled receptor) and beta (a Gs coupled receptor), and each can be further divided into subtypes . The different subtypes can coexist in some tissues, but one subtype normally predominates.

There are three subtypes of beta adrenoceptors (beta 1-3), the division is mainly based on their affinities to adrenergic agonists and antagonists. All three subtypes act in the main by activating a Gs protein , activating adenylate cyclase activity. The beta 2 subtype also couples to Gi/o protein . Beta adrenoceptor selective agonists (beta blockers) are used in the treatment of asthma, angina, cardiac conditions and have proven useful in the treatment of migraine, anxiety disorders and hyperthyroidism, and, when applied topically, are useful in the treatment of glaucoma .

This entry represents beta 3 adrenoceptors. They have limited distribution compared with the other beta adrenoceptors. They are expressed predominately in adipose tissue and the gastrointestinal tract , where they regulates lipolysis, thermogenesis and gut motility . They appear to coexist with beta 2 adrenoceptors in skeletal muscle, where the latter predominate .
Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT)
Type: Family

Protein-L-isoaspartate(D-aspartate) O-methyltransferase (

) (PCMT) (which is also known as L-isoaspartyl protein carboxyl methyltransferase) is an enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to the free carboxyl groups of D-aspartyl or L-isoaspartyl residues in a variety of peptides and proteins. The enzyme does not act on normal L-aspartyl residues L-isoaspartyl and D-aspartyl are the products of the spontaneous deamidation and/or isomerisation of normal L-aspartyl and L-asparaginyl residues in proteins. PCMT plays a role in the repair and/or degradation of these damaged proteins; the enzymatic methyl esterification of the abnormal residues can lead to their conversion to normal L-aspartyl residues. The SAM domain is present in most of these proteins.
Gfo/Idh/MocA-like oxidoreductase, N-terminal (Gfo/Idh/MocA-like_OxRdtase_N)
Type: Domain

This entry represents the N-terminal domain of a group of enzymes that utilise NADP or NAD, known as the GFO/IDH/MOCA family (GFO: glucose--fructose oxidoreductase, IDH: inositol 2-dehydrogenase and MOCA which catalyses a dehydrogenase reaction involved in rhizopine catabolism) in UniProtKB/Swiss-Prot, which includes enzymes that catalyse different chemical reactions such as oxidation and reduction of carbohydrates, oxidation of trans-dihydrodiols, reduction of biliverdin and hydrolysation of glycosidic bonds . Other proteins belonging to this family include Gal80, a negative regulator for the expression of lactose and galactose metabolic genes, although it does not have enzymatic activity; and several hypothetical proteins from yeast, Escherichia coli and Bacillus subtilis.

The Gfo/Idh/MocA protein family members have very low sequence identity but the 3D structures of the proteins are very similar, consisting of two main domains: an N-terminal dinucleotide-binding domain containing a typical Rossmann fold3 and a C-terminal α/β-domain participating in substrate binding and oligomerisation .
RNA polymerase II, heptapeptide repeat, eukaryotic (RNA_pol_II_repeat_euk)
Type: Repeat

RNA polymerase II (

) is one of the three forms of RNA polymerase that exist in eukaryotic nuclei. The C-terminal region of the largest subunit of this oligomeric enzyme consists of the tandem repeat of a conserved heptapeptide . The number of repeats varies according to the species (for example there are 17 in Plasmodium, 26 in yeast, 44 in Drosophila, and 52 in mammals). The region containing these repeats is essential for the function of polymerase II. This repeated heptapeptide
(called CT7n or CTD) is rich in hydroxyl groups. It probably projects out of the globular catalytic domain and may interact with the acidic activator domains of transcriptional regulatory proteins. It is also known to bind by intercalation to DNA. RNA polymerase II is activated by phosphorylation. The serine and threonine residues in the CT7n repeats are the target of such phosphorylation.
Ribulose bisphosphate carboxylase, large subunit, C-terminal (RuBisCO_lsu_C)
Type: Domain

Ribulose bisphosphate carboxylase (RuBisCO) catalyses the initial step in Calvin's reductive pentose phosphate cycle in plants as well as purple and green bacteria. It catalyzes the primary CO2 fixation step. RuBisCO consists of a large catalytic unit and a small subunit of undetermined function. In plants, the large subunit is coded by the chloroplastic genome while the small subunit is encoded in the nuclear genome. Rubisco is activated by carbamylation of an active site lysine, stabilized by a divalent cation, which then catalyzes the proton abstraction from the substrate ribulose 1,5 bisphosphate (RuBP) and leads to the formation of two molecules of 3-phosphoglycerate .
Fanconi anaemia group C protein (FANCC)
Type: Family

Fanconi anemia (FA) is a human disorder characterised by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. The FA complex repairs the interstrand cross-linking (ICL) lesions and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. It is required for the monoubiquitylation of FANCD2 and FANCI heterodimer. The FA core complex consists of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FANCT (UBET2), FAAP100 and FAAP24 .

This entry represents FANCC .