SII-SWORD/CoKE huggingface dataset:
P2X purinoreceptor (P2X_purnocptor)
Type: Family

This entry represents all P2X purinoreceptor subtypes.

P2X purinoceptors are cell membrane ion channels, gated by adenosine 5'-triphosphate (ATP) and other nucleotides; they have been found to be widely expressed on mammalian cells, and, by means of their functional properties, can be differentiated into three sub-groups. The first group is almost equally well activated by ATP and its analogue alpha,betamethylene-ATP, whereas, the second group is not activated by the latter compound. A third type of receptor (also called P2Z) is distinguished by the fact that repeated or prolonged agonist application leads to the opening of much larger pores, allowing large molecules to traverse the cell membrane. This increased permeability rapidly leads to cell death, and lysis.

Molecular cloning studies have identified seven P2X receptor subtypes, designated P2XR1-P2XR7, however, P2X1R, P2X2R, P2X3R, P2X4R, and P2X7R are functional . These receptors are proteins that share 35-48% amino acid identity, and possess two putative transmembrane (TM) domains, separated by a long (~270 residues) intervening sequence, which is thought to form an extracellular loop. Around 1/4 of the residues within the loop are invariant between the cloned subtypes, including 10 characteristic cysteines.

Studies of the functional properties of heterologously expressed P2X receptors, together with the examination of their distribution in native tissues, suggests they likely occur as both homo-and hetero multimers in vivo . Stimulation of these receptors induces changes in intracellular ion homeostasis leading to multiple key responses crucial for initiation, propagation, and resolution of inflammation . The P2X7 subtype has an important role in the activation of lymphocyte, granulocyte, macrophage and dendritic cell responses and, therefor, it may be a promising target for anti-inflammatory therapies.
Muscarinic acetylcholine receptor M4 (Musac_Ach_M4_rcpt)
Type: Family

Muscarinic acetylcholine receptors are members of rhodopsin-like G-protein coupled receptor family. They play several important roles; they mediate many of the effects of acetylcholine in the central and peripheral nervous system and modulate a variety of physiological functions, such as airway, eye and intestinal smooth muscle contraction, heart rate and glandular secretions. The receptors have a widespread tissue distribution and are a major drug target in human disease. They may be effective therapeutic targets in Alzheimer's disease, schizophrenia, Parkinson's disease and chronic obstructive pulmonary disease .

The muscarinic acetylcholine M4 receptor is primarily found in the CNS , its distribution largely overlapping with that of M1 and M3 subtypes. M4 receptors function as inhibitory autoreceptors for acetylcholine , activation of which inhibits acetylcholine release in the striatum.

Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission and activation of M4 receptors in the striatum inhibits dopamine-induced locomotor stimulation in mice . M4 receptor-deficient mice exhibit increased locomotor simulation in response to dopamine agonists, such as amphetamine and cocaine . Neurotransmission in the striatum influences extrapyramidal motor control. Therefore, alterations in M4 receptor activity may contribute to conditions such as Parkinson's Disease .
Oxidoreductase FAD/NAD(P)-binding (OxRdtase_FAD/NAD-bd)
Type: Domain

Bacterial ferredoxin-NADP
+
reductase may be bound to the thylakoid membrane or anchored to the thylakoid-bound phycobilisomes.
Chloroplast ferredoxin-NADP
+
reductase (

) may play a key role in regulating the relative amounts of cyclic and non-cyclic electron flow to meet the demands of the plant for ATP and reducing power. It is involved in the final step in the linear photosynthetic electron transport chain and has also been implicated in cyclic electron flow around photosystem I where its role would be to return electrons from ferredoxin to the cytochrome B-F complex.

This domain is present in a variety of proteins that include, bacterial flavohemoprotein, mammalian NADH-cytochrome b5 reductase, eukaryotic NADPH-cytochrome P450 reductase, nitrate reductase from plants, nitric-oxide synthase, bacterial vanillate demethylase, as well as others.
Large cysteine-rich periplasmic protein OmcB-like, DUF11 domain (OmcB-like_DUF11)
Type: Domain

This entry represents DUF11 domain found in large cysteine-rich periplasmic protein OmcB proteins from bacteria and archaea. It adopts an Ig-like fold.

Some members contain conserved N-terminal lysine and C-terminal asparagine with central aspartate/glutamate suggesting that these domains may contain an isopeptide bond.

In C. trachomatis, three cysteine-rich proteins (also believed to be lipoproteins), MOMP, OMP6 and OMP3, make up the extracellular matrix of the outer membrane . They are involved in the essential structural integrity of both the elementary body (EB) and reticulate body (RB) phase. They are thought to be involved in porin formation and, as these bacteria lack the peptidoglycan layer common to most Gram-negative microbes, such proteins are highly important in the pathogenicity of the organism.

In Methanothermobacter sp. CaT2, a DUF11-containing repeat hypothetical protein encoded by MTCT_1020 plays a key role as a membrane-bound adhesion protein in the aggregation of CaT2. DUF11-containing repeat domains are not involved in aggregation, but may be important for stabilizing the surface cell wall structures of CaT2 .
Adenosine A2B receptor (Adeno_A2B_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 .

In addition to their role in energy metabolism, purines (especially adenosine and adenine nucleotides) produce a wide range of pharmacological effects mediated by activation of cell surface receptors. Distinct receptors exist for adenosine. In the periphery, the main effects of adenosine include vasodilation, bronchoconstriction, immunosuppresion, inhibition of platelet aggregation, cardiac depression, stimulation of nociceptive afferents, inhibition of neurotransmitter release and inhibition of the release of other factors, e.g. hormones. In the CNS, adenosine exerts a pre- and post-synaptic depressant action, reducing motor activity, depressing respiration, inducing sleep and relieving anxiety. The physiological role of adenosine is thought to be to adjust energy demands in line with oxygen supply. Many of the clinical actions of methylxanthines are thought to be mediated through antagonism of adenosine receptors. Four subtypes of receptor have been identified, designated A1, A2A, A2B and A3.

A2B receptors are widespread in the human brain relative to A2A receptors. By contrast, however, in the rat its mRNA is found only in low levels in the brain and it has a unique distribution in the periphery, high levels occurring in the intestine and bladder. The receptor stimulates cAMP through G proteins.
Alpha crystallin/Small heat shock protein, animal type (Alpha-crystallin/sHSP_animal)
Type: Family

This entry represents a group of alpha-crystallin domain containing proteins from animals, including the A and B subunits (or chains) of alpha-crystallin and related small heat shock proteins.

HSPs can be divided into HSP100, HSP90, HSP70, HSP60, HSP40 and small heat shock proteins (sHSPs) according to their molecular weight and homology. Small heat shock proteins contain an alpha-crystallin domain and variable N- and C-terminal extensions. sHsps are generally active as large oligomers consisting of multiple subunits, and are believed to be ATP-independent chaperones that prevent aggregation and are important in refolding in combination with other Hsps .

The crystallins are water-soluble structural proteins that occur in high concentration in the cytoplasm of eye lens fibre cells. Four major groups of crystallin have been distinguished on the basis of size, charge and immunological properties: alpha-, beta-and gamma-crystallins occur in all vertebrate classes (though gamma-crystallins are low or absent in avian lenses); and delta-crystallin is found exclusively in reptiles and birds .

Alpha-crystallin occurs as large aggregates, comprising two types of related subunits or chains (A and B) that are highly similar to the small (15-30kDa) heat shock proteins (HSPs), particularly in their C-terminal halves. The relationship between these families is one of classic gene duplication and divergence, from the small HSP family, allowing adaptation to novel functions. Divergence probably occurred prior to evolution of the eye lens, alpha-crystallin being found in small amounts in tissues outside the lens .

Alpha-crystallin has chaperone-like properties including the ability to prevent the precipitation of denatured proteins and to increase cellular tolerance to stress . It has been suggested that these functions are important for the maintenance of lens transparency and the prevention of cataracts. This is supported by the observation that alpha-crystallin mutations show an association with cataract formation.
Transcription elongation factor, GreA/GreB, C-terminal (Tscrpt_elong_fac_GreA/B_C)
Type: Domain

Bacterial proteins GreA and GreB are necessary for efficient RNA polymerase transcription elongation past template-encoded arresting sites. Arresting sites in DNA have the property of trapping a certain fraction of elongating RNA polymerases that pass through, resulting in locked DNA/RNA/ polymerase ternary complexes. Cleavage of the nascent transcript by cleavage factors, such as GreA or GreB, allows the resumption of elongation from the new 3' terminus . Escherichia coli GreA and GreB are sequence homologues and have homologues in every known bacterial genome . GreA induces cleavage two or three nucleotides behind the terminus and can only prevent the formation of arrested complexes while greB releases longer sequences up to eighteen nucleotides in length and can rescue preexisting arrested complexes. These functional differences correlate with a distinctive structural feature, the distribution of positively charged residues on one face of the N-terminal coiled coil. Remarkably, despite close functional similarity, the prokaryotic Gre factors have no sequence or structural similarity with eukaryotic TFIIS.
Hyaluronidase PH20/Hyaluronidase-5 (Hyaluronidase_PH20/Hyal5)
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.

Family 56 (

) encompasses a group of hyaluronidases (

) that includes venom hyaluronidases and mammalian sperm surface proteins (PH-20 and hyaluronidase-5) .

PH-20 is required for sperm adhesion to the egg zona pellucida; it is located on both the sperm plasma membrane and acrosomal membrane . During fertilisation, sperm must first penetrate a layer of cumulus cells that surrounds the egg, before reaching the zona pellucida. The cumulus cells are embedded in a matrix containing hyaluronic acid, which is formed prior to ovulation. PH-20 facilitates penetration of the cumulus cell layer by digesting hyaluronic acid . The amino acid sequence of the mature protein contains approximately 460 amino acids, and includes six potential N-linked glycosylation sites and twelve cysteines, eight of which are tightly clustered near the C terminus .
Decaprenyl diphosphate synthase-like (UPP_synth-like)
Type: Family

In prokaryotes, undecaprenyl diphosphate synthase (UPP synthase, di-trans-poly-cis-decaprenylcistransferase or ditrans,polycis-undecaprenyl-diphosphate synthase (

)), catalyzes the formation of the carrier lipid undecaprenyl pyrophosphate (UPP) in bacterial cell wall peptidoglycan biosynthesis from isopentenyl pyrophosphate (IPP) . Cis (Z)-Isoprenyl diphosphate synthase (cis-IPPS) catalyzes the successive 1'-4 condensation of the IPP molecule to trans,trans-farnesyl diphosphate (FPP) or to cis,trans-FPP to form long-chain polyprenyl diphosphates. A few can also catalyze the condensation of IPP to trans-geranyl diphosphate to form the short-chain cis,trans- FPP. cis-IPPS form homodimers and are mechanistically and structurally distinct from trans-IPPS, which lack the DDXXD motifs, yet require Mg
2+
for activity. Homologues are also found in archaebacteria and include a number of uncharacterised proteins including some from yeasts.

This entry also matches related enzymes that transfer alkyl groups, such as dehydrodolichyl diphosphate synthase from eukaryotes, which catalyzes the formation of the polyisoprenoid glycosyl carrier lipid dolichyl monophosphate.
Collagen IV, non-collagenous (Collagen_IV_NC)
Type: Domain

Collagens are major components of the extracellular matrices of all metazoan life and play crucial roles in developmental processes and tissue homeostasis. Collagens are composed of three polypeptide chains (alpha chains) that fold together to form the characteristic triple helical collagenous domain. Some types of triple helical protomers contain genetically identical alpha chains forming homotrimers, whereas others contain two or three different alpha chains forming heterotrimers. The sequences required to form a collagenous domain are Gly-X-Y repeats in which the X and Y positions are frequently proline and hydroxyproline. Glycine is required every third residue as it is the only amino acid small enough to pack into the central core of the triple helix. The triple helix-forming parts are surrounded by non-collagenous (NC) domains of variable sequence, size, and shape. Even if the triple helical parts represent the most striking feature of collagens, tissue specificity as well as defined binding of non-collagens seem to be encoded in the NC domains. The terminal NC domains are excised, modified, or incorporated directly into the final suprastructure, depending on protomer type and function .

Type IV collagen is one of the major constituents of basement membranes, a specialised form of extracellular matrix underlying epithelia that compartmentalises tissues and provides molecular signals for influencing cell behaviour. Each type IV chain contains a long triple-helical collagenous domain flanked by a short 7S domain of 25 residues and a globular non-collagenous NC1 domain of ~230 residues at the N and C terminus, respectively. In protomer assembly, the NC1 domains (monomers) of three chains interact, forming an NC1 trimer, to select and register chains for triple helix formation. In network assembly, the NC1 trimers of two protomers interact, forming a NC1 hexamer structure, to select and connect protomers .

This duplicated domain is present at the C-terminal of type 4 collagen, the major structural component of glomerular basement membranes (GMB) forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen. Mutations in alpha-5 collagen IV are associated with
X-linked Alport syndrome.
Staphylocoagulase repeat (Staphylcoagulase_rpt)
Type: Repeat

Staphylocoagulase is an extracellular protein produced by several strains of Staphylococcus aureus and which specifically forms a complex with prothrombin . This complex named staphylothrombin can clot fibrinogen without any proteolytic cleavage of prothrombin. The C terminus of staphylocoagulase contains the tandem repeat which does not seem to be required for the procoagulant activity.
Flagellar basal body rod protein, N-terminal (Flag_bb_rod_N)
Type: Domain

Many bacterial species swim actively by means of flagella. The flagella organelle is made of three parts: the basal body, the hook and the filament. The basal body consists of four rings (L,P,S, and M) mounted on a central rod .

In Salmonella typhimurium and related organisms the rod has been shown to consist of four different, yet evolutionary related proteins: in the distal portion of the rod there are about 26 subunits of protein flgG and in the proximal portion there are about six subunits each of proteins flgB, flgC, and flgF. These four proteins contain a highly conserved asparagine-rich domain at their N terminus.
Acetylcholinesterase, insect (Acylcholinesterase_insect)
Type: Family

Cholinesterase enzymes are members of the broader alpha/beta hydrolase family and can be dividied into two distinct groups: those that catalyse the hydrolysis of acetylcholine to choline and acetate (acetylcholinesterases

)

acetylcholine + H
2
O ->choline + acetate

and those that catalyse the conversion of other acylcholines to a choline and a weak acid (cholinesterases

)

an acylcholine + H
2
O ->choline + a carboxylate

Acetylcholinesterase also acts on a variety of acetic esters and catalyses transacetylations. It is the most intensively studied of the cholinesterase enzymes due to its key physiological role in the turnover of the neurotransmitter acylcholine . This enzyme is found in, or attached to, cellular or basement membranes of presynaptic cholinergic neurons and postsynaptic cholinoceptive cells within the neuromuscular junction. Signal transmission at the neuromuscular junction involves the release of acylcholine, its interaction with the acycholine receptor and hydrolysis, all occuring in a period of a few milliseconds. Rapid hydrolysis of the newly released aceytlcholine is vital in order to prevent continuous firing of the nerve impulses . Consistent with its role in this process, acetylcholinesterase has an unusually high turnover number, ensuring that acetylcholine is broken down quickly. There is evidence to suggest that acetylcholinesterase has additional important roles including involvement in neuronal adhesion, the formation of Alzheimer fibrils, and neurite growth .

Insect acetylcholinesterase is often targeted by insecticides, especially in the effort to eradicate mosquitos from certain areas of the world .
5-lipoxygenase-activating protein (5_LipOase_AP)
Type: Family

5-lipoxygenase-activating protein (FLAP) is an integral membrane protein found in cells that produce leukotrienes, the biologically active metabolites of arachidonic acid that have been implicated in a variety of inflammatory responses, including asthma, arthritis and psoriasis .

FLAP appears to activatate 5-lipoxygenase (5LOX) by facilitating its binding to membranes . It binds arachidonic acid, and may play a role in its transfer to 5LOX. The protein has been shown to bind to MK-886, a compound that blocks leukotriene biosynthesis .
Arylamine N-acetyltransferase (Arylamine_N-AcTrfase)
Type: Family

Arylamine N-acetyltransferase (NAT) facilitates the transfer of an acetyl group from acetyl coenzyme A on to a wide range of arylamine, N-hydroxyarylamines and hydrazines. Acetylation of these compounds generally results in inactivation. NAT is found in many species from Mycobacteria (Mycobacterium tuberculosis, Mycobacterium smegmatis etc) to Homo sapiens (Human). It was the first enzyme to be observed to have polymorphic activity amongst human individuals. NAT is also responsible for the inactivation of Isoniazid (a drug used to treat tuberculosis) in humans . NAT catalyses the reaction:

Acetyl-coA + arylamine = coA + N-acetylarylamine

NAT is the target of a common genetic polymorphism of clinical relevance in humans. The N-acetylation polymorphism is determined by low or high NAT activity in liver. NAT has been implicated in the action and toxicity of amine-containing drugs, and in the susceptibility to cancer and systematic lupus erythematosus . Two highly similar human genes for NAT, termed NAT1 and NAT2, encode genetically invariant and variant NAT proteins, respectively. The structure of both proteins is similar to each other and to their prokaryotic orthologues, showing three domains: the N-terminal domain is mostly α-helical, the central domain consists of nine β-strands and the C-terminal has has four anti-parallel β-strands and one α-helix. However, in the human central domain there is a specific insertion .
Small acid-soluble spore protein, alpha/beta-type (SASP_alpha/beta-type)
Type: Family

Small, acid-soluble spore proteins (SASP or ASSP) are proteins bound to the spore DNA of bacteria of the genera Bacillus, Thermoactynomycetes, and Clostridium . They are double-stranded DNA-binding proteins that cause DNA to change to an A-like conformation. They protect the DNA backbone from chemical and enzymatic cleavage and are thus involved in dormant spore's high resistance to UV light. SASP are degraded in the first minutes of spore germination and provide amino acids for both new protein synthesis and metabolism.

There are two distinct families of SASP: the α/β type and the gamma-type. Alpha/beta SASP are small proteins of about sixty to seventy amino acid residues that are generally coded by a multigene family. The N terminus of alpha/beta SASP contains the site which is cleaved by a SASP-specific protease that acts during germination while the C terminus and is probably involved in DNA-binding.
Hexapeptide repeat (Hexapep)
Type: Repeat

A variety of bacterial transferases contain a repeat structure composed of tandem repeats of a [LIV]-G-X(4) hexapeptide, which, in the tertiary structure of LpxA (Acyl-[acyl-carrier-protein]-UDP-N-acetylglucosamine O-acyltransferase) , has been shown to form a left-handed parallel β-helix. A number of different transferase protein families contain this repeat, such as the bifunctional protein GlmU, galactoside acetyltransferase-like proteins , the gamma-class of carbonic anhydrases , and tetrahydrodipicolinate-N-succinlytransferases (DapD), the latter containing an extra N-terminal 3-helical domain . It has been shown that most hexapeptide acyltransferases form catalytic trimers with three symmetrical active sites .