SII-SWORD/CoKE huggingface dataset:
ATPase, F1/V1/A1 complex, alpha/beta subunit, nucleotide-binding domain (ATPase_F1/V1/A1_a/bsu_nucl-bd)
Type: Domain

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

The F-ATPases (or F1F0-ATPases), V-ATPases (or V1V0-ATPases) and A-ATPases (or A1A0-ATPases) are composed of two linked complexes: the F1, V1 or A1 complex contains the catalytic core that synthesizes/hydrolyses ATP, and the F0, V0 or A0 complex that forms the membrane-spanning pore. The F-, V- and A-ATPases all contain rotary motors, one that drives proton translocation across the membrane and one that drives ATP synthesis/hydrolysis .

In F-ATPases, there are three copies each of the alpha and beta subunits that form the catalytic core of the F1 complex, while the remaining F1 subunits (gamma, delta, epsilon) form part of the stalks. There is a substrate-binding site on each of the alpha and beta subunits, those on the beta subunits being catalytic, while those on the alpha subunits are regulatory. The alpha and beta subunits form a cylinder that is attached to the central stalk. The alpha/beta subunits undergo a sequence of conformational changes leading to the formation of ATP from ADP, which are induced by the rotation of the gamma subunit, itself driven by the movement of protons through the F0 complex C subunit .

In V- and A-ATPases, the alpha/A and beta/B subunits of the V1 or A1 complex are homologous to the alpha and beta subunits in the F1 complex of F-ATPases, except that the alpha subunit is catalytic and the beta subunit is regulatory.

The structure of the alpha and beta subunits is almost identical. Each subunit consists of a N-terminal β-barrel, a central domain containing the nucleotide-binding site and a C-terminal α-bundle domain . This entry represents the central domain. It is found in the alpha and beta subunits from F1, V1, and A1 complexes, as well as in flagellar ATPase and the termination factor Rho.
Rab-GAP-TBC domain (Rab-GAP-TBC_dom)
Type: Domain

The ~200 amino acid TBC/rab GTPase-activating protein (GAP) domain is well conserved across species and has been found in a wide range of different proteins from plant adhesion molecules to mammalian oncogenes. The name TBC derives from the name of the murine protein Tbc1 in which this domain was first identified based on its similarity to sequences in the tre-2 oncogene, and the yeast regulators of mitosis, BUB2 and cdc16 . The connection of this domain with rab GTPase activation stems from subsequent in-depth sequence analyses and alignments and recent work demonstrating that it appears to contain the catalytic activities of the yeast rab GAPs, GYP1, and GYP7 .

The TBC/rab GAP domain has also been named PTM after three proteins known to contain it: the Drosophila pollux, the human oncoprotein TRE17 (oncoTRE17), and a myeloid cell line-expressed protein . The TBC/rab GAP domain contains six conserved motifs named A to F . A conserved arginine residue in the sequence motif B has been shown to be critical for the full GAP activity . Resolution of the 3D structure of the TBC/rab GAP domain of GYP1 has shown that it is a fully α-helical V-shaped molecule. The conserved arginine residue is positioned at the side of the narrow cleft on the concave site of the V-shaped molecule. It has been proposed that this cleft is the binding site for the GTPase. The conserved arginine residue probably functions as a catalytic arginine finger analogous to that seen in ras and Rho-GAPs. The two key features of the arginine finger activation mechanism appear to be (i) the positioning of the catalytically essential GTPase glutamine side chain via a hydrogen bonding interaction between the glutamine carbamoyl-NH2 group and the main chain carbonyl group of the GAP arginine, and (ii) the polarization of the gamma-phosphate group or the stabilization of charge on it via the interaction of the positively charged side chain guanidinoyl group of the GAP arginine .
Large ribosomal subunit protein eL19 domain (Ribosomal_eL19_dom)
Type: Domain

This entry represents a structural domain of large ribosomal subunit protein eL19, found in archaea and eukaryotes .
Zinc finger, TAZ-type (Znf_TAZ)
Type: Domain

TAZ (Transcription Adaptor putative Zinc finger) domains are zinc-containing domains found in the homologous transcriptional co-activators CREB-binding protein (CBP) and the P300. CBP and P300 are histone acetyltransferases (

) that catalyse the reversible acetylation of all four histones in nucleosomes, acting to regulate transcription via chromatin remodelling. These large nuclear proteins interact with numerous transcription factors and viral oncoproteins, including p53 tumour suppressor protein, E1A oncoprotein, MyoD, and GATA-1, and are involved in cell growth, differentiation and apoptosis . Both CBP and P300 have two copies of the TAZ domain, one in the N-terminal region, the other in the C-terminal region. The TAZ1 domain of CBP and P300 forms a complex with CITED2 (CBP/P300-interacting transactivator with ED-rich tail), inhibiting the activity of the hypoxia inducible factor (HIF-1alpha) and thereby attenuating the cellular response to low tissue oxygen concentration . Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators .

Proteins containing this domain also include a group of land-plant specific proteins, know as the BTB/POZ and TAZ domain-containing (BT) protein. The reports of their interaction with CUL3 are contradictory. They are multifunctional scaffold proteins essential for male and female gametophyte development .

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Rho GTPase-activating protein domain (RhoGAP_dom)
Type: Domain

Members of the Rho family of small G proteins transduce signals from plasma-membrane
receptors and control cell adhesion, motility and shape by actin cytoskeleton formation.
Like all other GTPases, Rho proteins act as molecular switches, with an active
GTP-bound form and an inactive GDP-bound form. The active conformation is promoted by
guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins
(GAPs) which stimulate the intrinsic GTPase activity of small G proteins.
This entry is a Rho/Rac/Cdc42-like GAP domain, that is found in a wide variety of large,
multi-functional proteins .
A number of structure are known for this family
.
The domain is composed of seven α-helices.
This domain is also known as the breakpoint cluster region-homology (BH) domain.
Peptidase C3A/C3B, picornaviral (Peptidase_C3A/C3B_picornavir)
Type: Domain

Viruses in the order Picornavirales infect different vertebrate, invertebrate, and plant hosts and are responsible for a variety of human, animal, and plant diseases. These viruses have a single-stranded, positive sense RNA genome that generally translates a large precursor polyprotein which is proteolytically cleaved after translation to generate mature functional viral proteins. This process is usually mediated by (more than one) proteases, and a 3C (for the family Picornaviridae) or 3C-like (3CL) protease (for other families) plays a central role in the cleavage of the viral precursor polyprotein. In addition to this key role, 3C/3C-like protease is able to cleave a number of host proteins to remodel the cellular environment for virus reproduction . The Picornavirales 3C/3C-like protease domain forms the MEROPS peptidase family C3 (picornain family) of clan PA.

The 3C/3CL protease domain adopts a chymotrypsin-like fold with a cysteine nucleophile in place of a commonly found serine which suggests that the cysteine and serine perform an analogous catalytic function. The catalytic triad is made of a histidine, an aspartate/glutamate and the conserved cysteine in this sequential order. The 3C/3CL protease domain folds into two antiparallel β barrels that are linked by a loop with a short α-helix in its middle, and flanked by two other α-helices at the N- and C-terminal. The two barrels are topologically equivalent and are formed by six antiparallel β strands with the first four organised into a Greek key motif. The active-site residues are located in the cleft between the two barrels with the nucleophilic Cys from the C-terminal barrel and the general acid base His-Glu/Asp from the N-terminal barrel .

This entry includes cysteine peptidases that belong to MEROPS peptidase family C3 (picornain, clan PA(C)), subfamilies C3A and C3B.
Hepadnaviral P protein, N-terminal (DNApol_viral_N)
Type: Domain

This domain is at the N terminus of hepadnavirus P proteins and covers the so-called terminal protein and the spacer region of the protein. This domain is always associated with

and

.
GPCR, family 3, metabotropic glutamate receptor 5 (GPCR_3_mGluR5)
Type: Family

The mRNA for GRM5 is widespread in the brain, with a unique distribution; it is found in high levels in the striatum, cerebral cortex, hippocampus and olfactory bulb. GRM5 activates the phosphoinositide pathway. It plays an important role in the regulation of synaptic plasticity and the modulation of the neural network activity . Like GRM1 [

], it is a potential therapeutic target for several diseases with a similar structure to this seen in the entire GPCR superfamily .

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 .

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

The metabotropic glutamate receptors are functionally and pharmacologically distinct from the ionotropic glutamate receptors. They are coupled to G-proteins and stimulate the inositol phosphate/Ca
2+
intracellular signalling pathway . At least eight sub-types of metabotropic receptor (GRM1-8) have been identified in cloning studies. The sub-types differ in their agonist pharmacology and signal transduction pathways.
GPS motif (GPS)
Type: Conserved_site

The GPS motif is an integral part, and the most conserved region, of a much larger (320-residue approximately) domain that has been termed GPCR-Autoproteolysis INducing (GAIN) domain. The GAIN domain represents an autoproteolytic fold whose function is relevant for GPCR signalling and may regulate this process . The GPS motif is an essential element for receptor function and needs to be within the context of the GAIN domain to mediate autoproteolysis .

GPS (for GPCR proteolytic site) motif is found in a number of G-protein-coupled receptors (GPCRs) including CIRLs/latrophilins and in other membrane-associated proteins like the sea urchin receptor for egg jelly protein (REJ) .

For the CIRL-1, CIRL-2, CIRL-3 and CD-97 proteins, it has been shown that they are each made of two non-covalently bound subunits resulting from the endogenous proteolytic cleavage of a precursor protein. Because the cysteine-rich domain of CIRL-1 and possibly other receptors is involved in the endogenous proteolytic processing of CIRL-1 and possibly other receptors, it has been named GPS for GPCR proteolytic site. As the amino acids surrounding the putative cleavage site are the most conserved residues in the GPS domain, it has been suggested that all proteins containing it may be cleaved at this position .

GPS motifs are about 50 residues long and contain either 2 or 4 cysteine residues that are likely to form disulphide bridges. Based on conservation of these cysteines the following pairing can be predicted.

+-----------------+
| |
+-----------------+---------------+ |
| | | |
XXXCXXXXXXXXXXXXXXXXXCXXXXXXXXXXXXXXXCXCXXLTXXXXXXX
^
cleavage site
Orexin receptor family (Orexin_rcpt)
Type: Family

The neuropeptide hormone orexin stimulates appetite and food consumption , and is found in the hypothalamus, which has been shown to be the 'feeding centre' and plays a central role in the integrated control of feeding and energy homeostasis . It also has a prominent role in promoting wakefulness . The orexin receptor (also referred to as the hypocretin receptor) is a rhodopsin-like G protein-coupled receptor that binds orexin. There are two subtypes; orexin receptor 1 (OX1) and orexin receptor 2 (OX2) .

This entry represents the orexin receptor family.
Alpha 2B adrenoceptor (ADRA2B_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 subtpyes of alpha 2 adrenoceptors (2A-C). The receptors are usually found presynaptically, where they inhibit the release of noradrenaline, and thus serve as an important receptor in the negative feedback control of noradrenaline release . Postsynaptic alpha 2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of the receptors causes platelet aggregation , blood vessel constriction and constriction of vascular smooth muscle . Agonists of alpha 2 adrenergic receptors are frequently used in veterinary anaesthesia, where they affect sedation, muscle relaxation and analgesia through their effects on the CNS . Alpha 2 adrenoceptors are coupled through the Gi/Go mechanism, inhibiting adenylate cyclase activity and downregulating cAMP formation.

This entry represents the alpha 2B receptor. It is found in the kidney, brain, and spinal cord, along with the other alpha 2 subtypes. However, it is the only subtype to be found in the heart and liver. Peripheral tissues, predominantly express the alpha 2A and 2B subtypes, with little alpha 2C. This is in contrast to the CNS, where alpha 2A and 2C are predominantly expressed, with little alpha 2B .
RNA-directed RNA polymerase, fingers/palm subdomains, flavivirus (Flavi_RdRp_fingers/palm)
Type: Domain

Flaviviruses produce a polyprotein from the ssRNA genome. The polyprotein is cleaved to a number of products one of which is NS5. Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. NS5 is the largest mature viral protein and contains a N-terminal methyltransferase (MTase) domain separated by a short linker from the C-terminal RNA-directed RNA polymerase domain (RdRp) that adopts a characteristic right-handed fingers-palm-thumb fold and possesses a number of short regions and motifs homologous to other RNA-directed RNA polymerases . NS5 binds to a the stem loop A (SLA) at the 5' extremity of Flavivirus genome and regulates translation of the viral genome .

This entry represents the fingers and palm subdomains of RdRp, which contain the conserved polymerase motifs (A-G) from all RdRps.

RNA-directed RNA polymerase (RdRp) (

) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage . It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear.
The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product .
Peptidase S8/S53 domain (Peptidase_S8/S53_dom)
Type: Domain

These proteins contain a domain found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin) and S53 (sedolisin), both of which are members of clan SB .

The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence . It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses . The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase . Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity . Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein .

The proprotein-processing endopeptidases kexin, furin and related enzymes
form a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site . Members of the kexin subfamily, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of a cysteine near to the active site histidine . Only one viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish .
BTB/POZ domain (BTB/POZ_dom)
Type: Domain

The BTB domain (Broad-Complex, Tramtrack and Bric a brac) is also known as the POZ domain (POxvirus and Zinc finger). It is a homodimerisation domain occurring at the N terminus of proteins containing multiple copies of either zinc fingers of the C2H2 type or Kelch repeats . Many BTB proteins are transcriptional regulators that are thought to act through the control of chromatin structure.

The structure of the BTB domain of the promyelocytic leukaemia zinc finger (PLZF) protein has been determined by X-ray crystallography and reveals a tightly intertwined dimer with an extensive hydrophobic interface . A surface-exposed groove lined with conserved amino acids is formed at the dimer interface, suggesting a peptide-binding site.
Geminivirus BL1 movement protein (Gemini_BL)
Type: Family

The movement of bipartite Geminiviruses such as squash leaf curl virus (SqLCV) requires the cooperative interaction of two essential virus-encoded movement proteins, BR1 and BL1. Recent studies of SqLCV and bean dwarf mosaic virus have shown that BR1 and BL1 act in a cooperative manner to move the viral genome intracellularly from the nucleus to the cytoplasm and across the wall cell to cell. BR1 is a nuclear shuttle protein, and it has been proposed to bind newly replicated viral ssDNA genomes and move these between the nucleus and cytoplasm. These BR1-genome complexes are then directed to the cell periphery through interactions between BR1 and BL1, where, as the result of BL1 action, the complexes are moved to adjacent uninfected cells. The precise mechanism by which BL1 acts to transport these genome complexes across the cell wall, and whether this may differ in different cell types, remains at issue .
DNA helicase, UvrD/REP type (DNA_helicase_UvrD/REP)
Type: Family

Members of this family are helicases that catalyse ATP dependent unwinding of double stranded DNA to single stranded DNA. The family includes both Rep and UvrD helicases . The Rep family helicases are composed of four structural domains . The Rep proteins function as dimers.