SII-SWORD/CoKE huggingface dataset:
GDSL lipase/esterase (GDSL)
Type: Family

GDSL esterases and lipases are hydrolytic enzymes with multifunctional properties . This new subclass of lipolytic enzymes possesses a distinct GDSL sequence motif different from the GxSxG motif found in many lipases . Members include; Aeromonas hydrophila lipase, Vibrio mimicus lecithinase, Vibrio parahaemolyticus thermolabile haemolysin, rabbit phospholipase (AdRab-B), and Arabidopsis thaliana anter-specific proline-rich protein. 3D structures of several enzymes of this family revealed several β-strands and α-helices arranged in alternating order and the substrate-binding pocket between the central β-strand and long α-helix appears to be highly flexible .
Glycoside hydrolase, family 4 (Glyco_hydro_4)
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.

Glycoside hydrolase family 4 (

) is a protein family that comprises enzymes with several known activities; 6-phospho-beta-glucosidase (

); 6-phospho-alpha-glucosidase (

); alpha-galactosidase (

). These enzymes require both NAD(H) and divalent metal (such asMn2+, Fe2+, Co2+, or Ni2+) for its activity .
CXC chemokine (Chemokine_CXC)
Type: Family

Most members of this family of low-molecular weight proteins seem to have mitogenic, chemotactic or inflammatory activities. They are released by phagocytes, mesenchymal cells and a wide variety of tissue cells, upon exposure to inflammation . 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.

The family can be split into two groups, depending on the spacing of two N-terminal Cys residues: in one group (CxC), the cysteines are separated by a single amino acid; in the second (C-C), they are adjacent . The CxC group includes such factors as interleukin-8, platelet factor 4, melanoma growth stimulatory activity protein, macrophage inflammatory protein 2, platelet basic protein, and several others. The 'C-C' group includes the monocyte chemotactic proteins, macrophage inflammatory proteins, amongst others.

This entry represents the CxC family of chemokines.
Ephrin receptor ligand binding domain (Ephrin_rcpt_lig-bd_dom)
Type: Domain

The Eph receptors, which bind a group of cell-membrane-anchored ligands known as ephrins, represent the largest subfamily of receptor tyrosine kinases (RTKs). The Eph receptors and their ephrin ligands control a diverse array of cell-cell interactions in the nervous and vascular systems. On ephrin binding, the Eph kinase domain is activated, initiating 'forward' signaling in the receptor-expressing cells. Simultaneously, signals are also induced in the ligand-expressing cells a phenomenon referred to as 'reverse' signalling. The extracellular Eph receptor region contains a conserved 180- amino-acid N-terminal ligand-binding domain (LBD) which is both necessary and sufficient for bindings of the receptors to their ephrin ligands. An adjacent cysteine-rich region might be involved in receptor-receptor oligomerization often observed on ligand binding, whereas the next two fibronectin type III repeats have yet to be assigned a clear biological function. The cytoplasmic Eph receptor region contains a kinase domain, a sterile alpha motif (SAM) domain, and a PDZ-binding motif. The ligand-binding domain (LBD) of Eph receptors is unique to this family of RTKs ans shares no significant amino-acid-sequence homology with other known proteins .

The Eph LBD domain forms a compact globular structure which folds into a jellyroll β-sandwich composed of 11 antiparallel β-strands. It has two antiparallel β-sheets, with the usual left-handed twist, packed against each other to form a compact β-sandwich, and a short 3(10) helix .
Restriction/modification DNA-methyltransferase (RM_Methyltransferase)
Type: Family

Site-specific DNA-methyltransferase, N-6 adenine-specific DNA methylase (

) and cytosine-N4-specific (

) are enzymes that specifically methylate the amino group at the C-4 position of cytosines and the N-6 position of adenine in DNA. In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. There are two major classes of DNA methyltransferase that differ in the nature of the modifications they effect. The members of one class (C-MTases) methylate a ring carbon and form C5-methylcytosine and members of the second class (N-MTases) methylate exocyclic nitrogens and form either N4-methylcytosine (N4-MTases) or N6-methyladenine (N6-MTases). Both classes utilise the cofactor S-adenosyl-L-methionine (SAM) as the methyl donor and are active as monomeric enzymes. These proteins show three domains, two of them are conserved across multiple kingdoms (SAM binding and the catalytic domain) .
Flavodoxin-like (Flavdoxin-like)
Type: Domain

This entry includes flavodoxins and flavodoxin-like proteins, such as NADPH-dependent diflavin oxidoreductase NDOR1 and nitric oxide synthases.
Acetyl-CoA carboxylase, alpha subunit (Acetyl_CoA_COase_a_su)
Type: Family

This entry contains the alpha subunit (Acetyl-coenzyme A carboxylase carboxyl transferase ACCA

) of the acetyl coenzyme A carboxylase complex (

). ACCA catalyses the transfer of a carboxyl group carried on a biotinylated biotin carboxyl carrier protein (BCCP) to acetyl-CoA, forming malonyl-CoA, the first step in the synthesis of long-chain fatty acids. The acetyl-CoA carboxylase complex is a heterohexamer of biotin carboxyl carrier protein, biotin carboxylase and two non-identical carboxyl transferase subunits (alpha and beta) in a 2:2 association . The reaction involves two steps:

Biotin carrier protein + ATP + HCO
3
-
->Carboxybiotin carrier protein + ADP + P
i

Carboxybiotin carrier protein + Acetyl-CoA ->Malonyl-CoA + Biotin carrier protein
Chalcone/stilbene synthase, N-terminal (Chalcone/stilbene_synt_N)
Type: Domain

This entry represents the N-terminal domain of chalcone and stilbene synthases and related proteins.

Chalcone synthases (CHS) (

) and stilbene synthases (STS) (formerly known as resveratrol synthases) are related plant enzymes, members of the plant polyketide synthase superfamily. CHS is an important enzyme in flavonoid biosynthesis and STS is a key enzyme in stilbene-type phyloalexin biosynthesis. Both enzymes catalyse the addition of three molecules of malonyl-CoA to a starter CoA ester (a typical example is 4-coumaroyl-CoA), producing either a chalcone (with CHS) or stilbene (with STS) .

These enzymes have a conserved cysteine residue, located in the central section of the protein sequence, which is essential for the catalytic activity of both enzymes and probably represents the binding site for the 4-coumaryl-CoA group .
Pyridine nucleotide-disulphide oxidoreductase, class I (Pyr_nuc-diS_OxRdtase)
Type: Family

The pyridine nucleotide-disulphide reductases (PNDR) use the isoalloxazine ring of FAD to shuttle reducing equivalents from NAD(P)H to a Cys residue that is usually a part of a redox-active disulphide bridge. In a second step, the reduced disulphide reduces the substrate. On the basis of sequence and structural similarities , PNDR can be categorised into 2 groups.

Class I includes glutathione reductase, trypanothione reductase, lipoamide dehydrogenase and mercuric reductase. They cover a wide range of catalytic functions: glutathione reductase ensures that the cell has enough reduced glutathione to maintain protein thiol groups in the reduced state ; trypanothione reductase carries out the analogous reaction in trypanosomal cells (trypanothione is an analogue of glutathione) ; lipoamide dehydrogenase, the E3 component of alpha-ketoacid dehydrogenase multienzyme complex, oxidises the dihydrolypoyl groups of lipoate acyltransferase, and so couples glycolysis to the tricarboxylic acid cycle ; and mercuric reductase enables bacteria to detoxify the mercuric ion by reducing it to elemental mercury, which evaporates from the cell .
Plectin repeat (Plectin_repeat)
Type: Repeat

Plectin may have a role in cross-linking intermediate filaments, in inter-linking intermediate filaments with microtubules and microfilaments and in anchoring intermediate filaments to the plasma and nuclear membranes. Plectin is recruited into hemidesmosomes, multiprotein complexes that facilitate adhesion of epithelia to the basement membrane, thereby providing linkage between the intracellular keratin filaments to the laminins of the extracellular matrix. Plectin binds to hemidesmosomes through association of its actin-binding domain with the first pair of fibronectin type III repeats and a small part of the connecting segment of the integrin-beta4 subunit, the latter (integrin-alpha6,beta4) acting as a receptor for the extracellular matrix component laminin-5.

The plectin repeat is also seen in the cell adhesion junction plaque proteins, desmoplakin, envoplakin, and bullous pemphigoid antigen. The domains in plakins show considerable sequence homology. The N terminus consists of a plakin domain containing a number of subdomains with high α-helical content, while the central coiled-coil domain is composed of heptad repeats involved in the dimerisation of plakin, and the C terminus contains one or more homologous repeat sequences referred to plectin repeats . This entry represents the plectin repeats found in the C terminus of plakin proteins.
Transglutaminase, N-terminal (Transglutaminase_N)
Type: Domain

Synonym(s): Protein-glutamine gamma-glutamyltransferase, Fibrinoligase, TGase.
Androgen receptor (Andrgn_rcpt)
Type: Family

Steroid or nuclear hormone receptors (NRs) constitute an important super-family of transcription regulators that are involved in diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members include the steroid hormone receptors and receptors for thyroid hormone, retinoids and 1,25-dihydroxy-vitamin D3. The proteins function as dimeric molecules in the nucleus to regulate the transcription of target genes in a ligand-responsive manner .
3-oxo-5-alpha-steroid 4-dehydrogenase, C-terminal (3-oxo-5_a-steroid_4-DH_C)
Type: Domain

3-oxo-5-alpha-steroid 4-dehydrogenases,

catalyse the conversion of 3-oxo-5-alpha-steroid + acceptor to 3-oxo-delta(4)-steroid + reduced acceptor. The steroid 5-alpha-reductase enzyme is responsible for the formation of dihydrotestosterone, this hormone promotes the differentiation of male external genitalia and the prostate during foetal development . In humans mutations in this enzyme can cause a form of male pseudohermaphorditism in which the external genitalia and prostate fail to develop normally. A related steroid reductase enzyme, DET2, is found in plants such as Arabidopsis. Mutations in this enzyme cause defects in light-regulated development . This domain is present in both type 1 and type 2 forms.

This domain is also found in polyprenol reductase (SRD5A3;

), which is reduces the alpha-isoprene unit of polyprenol to form dolichol. Dolichol is required for the synthesis of a dolichol-linked monosaccharide and the oligosaccharide precursor used for N-glycosylation .

Another enzyme with this domain is very-long-chain enoyl-CoA reductase (TECR;

), which catalyses the last of the four reactions of the long-chain fatty acids elongation cycle by reducing the trans-2,3-enoyl-CoA fatty acid intermediate to an acyl-CoA that can be further elongated by entering a new cycle of elongation .
Thromboxane receptor (Thbox_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists. Moreover, many endogenous prostanoids undergo rapid metabolism, especially TXA2.
Aromatic amino acid lyase (Aromatic_Lyase)
Type: Family

This family includes phenylalanine ammonia-lyase, (PAL;

), histidine ammonia-lyase, (HAL;

), and tyrosine aminomutase, (

) .

PAL and HAL are members of the Lyase class I_like superfamily of enzymes that, catalyze similar beta-elimination reactions and are active as homotetramers. Both PAL and HAL contain a catalytic Ala-Ser-Gly triad that is post-translationally cyclised . PAL is a key biosynthetic catalyst in phenylpropanoid assembly in plants and fungi, and is involved in the biosynthesis of a wide variety of secondary metabolites such as flavanoids, furanocoumarin phytoalexins and cell wall components. These compounds are important for normal growth and in responses to environmental stress. HAL catalyses the first step in histidine degradation, the removal of an ammonia group from histidine to produce urocanic acid. The core domain in PAL and HAL share about 30% sequence identity, with PAL containing an additional approximately 160 residues extending from the common fold . Tyrosine 2,3-aminomutase has aminomutase activity and, to a much lesser extent, ammonia-lyase activity .

PAL is being explored as enzyme substitution therapy for Phenylketonuria (PKU), a disorder which involves an inability to metabolize phenylalanine. HAL failure in humans results in the disease histidinemia .
Band 7 domain (Band_7)
Type: Domain

The band-7 protein family comprises a diverse set of membrane-bound proteins characterised by the presence of a conserved domain, the band-7 domain, also known as SPFH or PHB domain . The exact function of the band-7 domain is not known, but examples from animal and bacterial stomatin-type proteins demonstrate binding to lipids and the ability to assemble into membrane-bound oligomers that form putative scaffolds . A variety of proteins belong to this family. These include the prohibitins, cytoplasmic anti-proliferative proteins and stomatin, an erythrocyte membrane protein. Bacterial HflC protein also belongs to this family.

Note: Band 4.1 and Band 7 proteins refer to human erythrocyte membrane proteins separated by SDS polyacrylamide gels and stained with coomassie blue .
Hydrogenase expression/formation protein, HupF/HypC (Hydrogenase_HupF/HypC)
Type: Family

The large subunit of [NiFe]-hydrogenase, as well as other nickel metalloenzymes, is synthesised as a precursor devoid of the metalloenzyme active site. This precursor then undergoes a complex post-translational maturation process that requires a number of accessory proteins. The hydrogenase expression/formation and maturation proteins (HupF/HypC) form a family of small proteins that are hydrogenase precursor-specific chaperones required for this maturation process . They are believed to keep the hydrogenase precursor in a conformation accessible for metal incorporation .
Uncharacterised protein family UPF0012, conserved site (UPF0012_CS)
Type: Conserved_site

A group of uncharacterised proteins share this well-conserved region centred on a cysteine residue. These proteins are a subset of the carbon-nitrogen hydrolase family indicating that these as yet uncharacterised proteins may be related to members of this family .
TGF-beta, propeptide (TGF-b_propeptide)
Type: Domain

TGF-beta is secreted as a latent complex, consisting of the TGF-beta dimer non-covalently bound to LAP (latency associated peptide) plus a latent TGF-beta binding protein (LTBP). After post-translational processing, TGF-beta binds non-covalently to LAP, a homodimer formed from the propeptide region of TGF-beta, to confer latency . Latent TGF-beta can then be targeted to the extracellular matrix (ECM) by LTBP. The LAP dimer is usually disulfide-bound to LTBP .

This entry represents the propeptide region of TGF-beta that forms LAP.
Adenylosuccinate synthetase (Adenylosuccinate_synthetase)
Type: Family

Adenylosuccinate synthetase (

) plays an important role in purine biosynthesis, by catalysing the GTP-dependent conversion of IMP and aspartic acid to AMP. IMP and L-aspartate are conjugated in a two-step reaction accompanied by the hydrolysis of GTP to GDP in the presence of Mg2+. In the first step, the r-phosphate group of GTP is transferred to the 6-oxygen atom of IMP. An aspartate then displaces this 6-phosphate group to form the product adenylosuccinate. Adenylosuccinate synthetase has been characterised from various sources ranging from Escherichia coli (gene purA) to vertebrate tissues. In vertebrates, two isozymes are present: one involved in purine biosynthesis and the other in the purine nucleotide cycle.

The crystal structure of adenylosuccinate synthetase from E. coli reveals that the dominant structural element of each monomer of the homodimer is a central β-sheet of 10 strands. The first nine strands of the sheet are mutually parallel with right-handed crossover connections between the strands. The 10th strand is antiparallel with respect to the first nine strands. In addition, the enzyme has two antiparallel β-sheets, comprised of two strands and three strands each, 11 α-helices and two short 3/10-helices. Further, it has been suggested that the similarities in the GTP-binding domains of the synthetase and the p21ras protein are an example of convergent evolution of two distinct families of GTP-binding proteins . Structures of adenylosuccinate synthetase from Triticum aestivum and Arabidopsis thaliana when compared with the known structures from E. coli reveals that the overall fold is very similar to that of the E. coli protein .
Alpha 1B adrenoceptor (ADRA1B_rcpt)
Type: Family

This entry represents the alpha 1B adrenoceptor. It is widely distributed, with high levels occurring in the CNS, mainly in the cerebral cortex and brainstem , and in peripheral tissues such as the kidney and lung . Alpha 1B adrenoceptor has been shown to couple to phospholipase A2 and cause the activation of this enzyme through a pertussis toxin-sensitive pathway in CHO cells .

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.

Alpha 1 adrenoceptors have the following subtypes: 1A, 1B and 1D. They are found in both the central and peripheral nervous system. In the CNS, they are found mostly postsynaptically and have an excitatory function. Peripherally, they are responsible for contraction and are situated on vascular and non-vascular smooth muscle and veins . In the liver, they cause hepatic glycogenolysis and potassium release. Alpha 1 adrenoceptors are coupled to Gq/11, which activates phospholipase C and produces inositol triphosphate (IP3), and diacylglycerol (DAG). These second messengers and cause release of calcium from intracellular stores in the sarcoplasmic reticulum and activation of protein kinase C, respectively. Alpha 1 adrenoceptors have been implicated in other signalling pathways, including arachadonic acid release.
Somatostatin receptor 1 (Somatstn_rcpt_1)
Type: Family

Somatostatin (SST), also known as somatotropin release-inhibiting factor (SRIF), is a hypothalamic hormone, a pancreatic hormone, and a central and peripheral neurotransmitter. Somatostatin has a wide distribution throughout the central nervous system (CNS) as well as in peripheral tissues, for example in the pituitary, pancreas and stomach. The various actions of somatostatin are mediated by a family of rhodopsin-like G protein-coupled receptors, which comprise of five distinct subtypes: Somatostatin receptor 1 (SSTR1), Somatostatin receptor 2 (SSTR2), Somatostatin receptor 3 (SSTR3), Somatostatin receptor 4 (SSTR4) and Somatostatin receptor 5 (SSTR5) . These subtypes are widely expressed in many tissues , and frequently multiple subtypes coexist in the same cell . The somatostatin receptor subtypes also share common signalling pathways, such as the inhibition of adenylyl cyclase , activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K+ channels (SSTR2, SSTR3, SSTR4, SSTR5) , to voltage-dependent Ca2+ channels (SSTR1, SSTR2) , to an Na+/H+ exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, SSTR2), phospholipase C (SSTR2, SSTR5), and phospholipase A2 (SSTR4) .

This entry represents SSTR1 . In humans, it is expressed at high levels in the jejunum and stomach, with lower levels in the pancreas, colon and kidney, but it is absent in the brain. Conversely, in rodent tissue, high levels are found in the brain, but are absent in peripheral tissues . All five human somatostatin receptors expressed in COS-7 cells are coupled to activation of phosphoinositide (PI)-specific PLC-beta; and Ca2+ mobilisation via pertussis toxin-sensitive G protein(s) with an order of potency of SSTR5 >SSTR2 >SSTR3 >SSTR4 >SSTR1 .