SII-SWORD/CoKE huggingface dataset:
RIO kinase (RIO_kinase)
Type: Domain

This entry represents RIO kinase, they exhibit little sequence similarity with eukaryotic protein kinases, and are classified as atypical protein kinases . The conformation of ATP when bound to the RIO kinases is unique when compared with ePKs, such as serine/threonine kinases or the insulin receptor tyrosine kinase, suggesting that the detailed mechanism by which the catalytic aspartate of RIO kinases participates in phosphoryl transfer may not be identical to that employed in known serine/threonine ePKs. Representatives of the RIO family are present in organisms varying from Archaea to humans, although the RIO3 proteins have only been identified in multicellular eukaryotes, to date.

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
Hydrogenase maturation factor HypA/HybF (HypA/HybF)
Type: Family

Bacterial membrane-bound nickel-dependent hydrogenases require a number of accessory proteins which are involved in their maturation . One of these proteins is generally known as HypA. HypA is a metallochaperone that binds nickel to bring it safely to its target. The nickel coordinates with four nitrogens within the protein. Four conserved cysteines towards the C terminus bind one zinc moiety, probably to stabilise the protein fold . In Helicobacter pylori, HypA is involved in the maturation of both hydrogenase and urease . Escherichia coli has two proteins that belong to this family, HypA and HybF . A homologue, MJ0214, has also been found in a number of archaeal species, including the genome of Methanocaldococcus jannaschii (Methanococcus jannaschii). Guanidine hydrolase-activating protein A (GhaA) from Synechocystis sp. is also included in this entry, as it shows similarity to HypA. GhaA is involved in the maturation of the nickel-dependent guanidine hydrolase GdmH .
Ubiquinone biosynthesis monooxygenase COQ6 (UbQ_mOase_COQ6)
Type: Family

Ubiquinone (Q) functions as an electron carrier in the respiratory chain in mitochondria. Q biosynthesis involves a series of enzymatic steps, which are catalysed by the enzymes COQ1-COQ8 in Saccharomyces cerevisiae (Baker's yeast). COQ6, or ubiquinone biosynthesis monooxygenase, is a flavin-dependent enzyme localised to the matrix side of the inner mitochondrial membrane that is required for one or more steps in Q biosynthesis . In mammals and yeast, this enzyme is responsible for the C5-ring hydroxylation during ubiquinone biosynthesis, catalysing the hydroxylation of 3-hexaprenyl-4-hydroxybenzoic acid (HHB) to 3-hexaprenyl-4,5-dihydroxybenzoic acid (DHHB) .
Matrin/U1-C, C2H2-type zinc finger (Matrin/U1-C_Znf_C2H2)
Type: Domain

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.

C2H2-type (classical) zinc fingers (Znf) were the first class to be characterised. They contain a short β-hairpin and an α-helix (β/β/α structure), where a single zinc atom is held in place by Cys(2)His(2) (C2H2) residues in a tetrahedral array. C2H2 Znf's can be divided into three groups based on the number and pattern of fingers: triple-C2H2 (binds single ligand), multiple-adjacent-C2H2 (binds multiple ligands), and separated paired-C2H2 . C2H2 Znf's are the most common DNA-binding motifs found in eukaryotic transcription factors, and have also been identified in prokaryotes . Transcription factors usually contain several Znf's (each with a conserved β/β/α structure) capable of making multiple contacts along the DNA, where the C2H2 Znf motifs recognise DNA sequences by binding to the major groove of DNA via a short α-helix in the Znf, the Znf spanning 3-4 bases of the DNA . C2H2 zinc fingers can also bind to RNA and protein targets .

A specific C2H2 Znf is conserved in matrin and several RNA-binding proteins. The Znf follows the general pattern C-x2-C-x(12,16)-H-x5-H, and is different from the 'classical' DNA-binding C2H2 Znf.
Proteinase inhibitor I16, Streptomyces subtilisin-type inhibitor (Prot_inh_I16_SSI)
Type: Family

The Streptomyces family of bacteria produce a number of proteinase inhibitors, which belong to MEROPS inhibitor family I16, clan IY. They are characterised by their strong activity towards subtilisin (MEROPS peptidase family S8,

) and are collectively known as Streptomyces subtilisin inhibitors (SSI). Some SSI also inhibit trypsin, chymotrypsin (MEROPS peptidase family S1,

) and griselysin (MEROPS peptidase family M4,

) . Mutation of the active site residue can influence inhibition specificity .

SSI is a homodimer, each monomer containing 2 anti-parallel β-sheets and 2 short α-helices. Protease binding induces the widening of a channel-like structure, in which hydrophobic side-chains are sandwiched between 2 lobes . Loss of the C-terminal tetrapeptide VFAF drastically reduces the inhibitory effect of the proteins when there is less than one molecule of inhibitor present per molecule of enzyme. This implies that the tetrapeptide is neccessary to maintain the correct 3D fold . Structural similarities between the primary and secondary contact loops of SSI, and the ovomucoid and pancreatic secretory trypsin inhibitor family suggest evolution of the 2 families from a common ancestor .
rRNA 2'-O-methyltransferase fibrillarin-like (Fibrillarin)
Type: Family

Fibrillarin (rRNA 2'-O-methyltransferase fibrillarin) is a component of a nucleolar small nuclear ribonucleoprotein (SnRNP) . It is a S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins. Site specificity is provided by a guide RNA that base pairs with the substrate and methylation occurs at a characteristic distance from the sequence involved in base pairing with the guide RNA . Fibrillarin is associated with U3, U8 and U13 small nuclear RNAs in mammals and is similar to the yeast NOP1 protein . It has a
well conserved sequence of around 320 amino acids, and contains 3 domains, an N-terminal Gly/Arg-rich
region; a central domain resembling other RNA-binding proteins and containing an RNP-2-like consensus
sequence; and a C-terminal α-helical domain. An evolutionarily related pre-rRNA processing protein,
which lacks the Gly/Arg-rich domain, has been found in various archaebacteria.
Sea anemone toxin (Anenome_toxin)
Type: Family

Sea anemones produce many different neurotoxins with related structure and function. Proteins
belonging to this family include the neurotoxins, of which there are several, including calitoxin and anthopleurin.
The neurotoxins bind specifically to the sodium channel, thereby delaying its inactivation during
signal transduction, resulting in strong stimulation of mammalian cardiac muscle contraction. Calitoxin 1, also known as Delta-hormotoxin-Cpt1b , has been found in neuromuscular preparations of crustaceans, where it increases transmitter release,
causing firing of the axons . Three disulphide bonds are present in Anthopleurin-B, also known as Delta-actitoxin-Axm1a .
WH1/EVH1 domain (WH1/EVH1_dom)
Type: Domain

The EVH1 (WH1, RanBP1-WASP) domain is found in multi-domain proteins implicated in a diverse range of signalling, nuclear transport and cytoskeletal events. This domain of around 115 amino acids is present in species ranging from yeast to mammals. Many EVH1-containing proteins associate with actin-based structures and play a role in cytoskeletal organisation. EVH1 domains recognise and bind the proline-rich motif FPPPP with low-affinity, further interactions then form between flanking residues .

WASP family proteins contain an EVH1 (WH1) in their N-terminals which bind proline-rich sequences in the WASP interacting protein. Proteins of the RanBP1 family contain a WH1 domain in their N-terminal region, which seems to bind a different sequence motif present in the C-terminal part of RanGTP protein .
Arrestin (Arrestin)
Type: Family

G protein-coupled receptors are a large family of signalling molecules that respond to a wide variety of extracellular stimuli. The receptors relay the information encoded by the ligand through the activation of heterotrimeric G proteins and intracellular effector molecules. To ensure the appropriate regulation of the signalling cascade, it is vital to properly inactivate the receptor. This inactivation is achieved, in part, by the binding of a soluble protein, arrestin, which uncouples the receptor from the downstream G protein after the receptors are phosphorylated by G protein-coupled receptor kinases. In addition to the inactivation of G protein-coupled receptors, arrestins have also been implicated in the endocytosis of receptors and cross talk with other signalling pathways. Arrestin (retinal S-antigen) is a major protein of the retinal rod outer segments. It interacts with photo-activated phosphorylated rhodopsin, inhibiting or 'arresting' its ability to interact with transducin . The protein binds calcium, and shows similarity in its C terminus to alpha-transducin and other purine nucleotide-binding proteins. In mammals, arrestin is associated with autoimmune uveitis.

Arrestins comprise a family of closely-related proteins that includes beta-arrestin-1 and -2, which regulate the function of beta-adrenergic receptors by binding to their phosphorylated forms, impairing their capacity to activate G(S) proteins; Cone photoreceptors C-arrestin (arrestin-X) , which could bind to phosphorylated red/green opsins; and Drosophila phosrestins I and II, which undergo light-induced phosphorylation, and probably play a role in photoreceptor transduction .

The crystal structure of bovine retinal arrestin comprises two domains of antiparallel β-sheets connected through a hinge region and one short α-helix on the back of the amino-terminal fold . The binding region for phosphorylated light-activated rhodopsin is located at the N-terminal domain, as indicated by the docking of the photoreceptor to the three-dimensional structure of arrestin.
RIH domain (RIH_dom)
Type: Domain

Ryanodine (RyR) and Inositol 1,4,5-trisphosphate (IP3) receptors are intracellular Ca
2+
-release channels. The RIH (RyR and IP3R Homology) domain is an extracellular domain from these two types of calcium channels. This domain may form a binding site for IP3 .
PAS-associated, C-terminal (PAS-assoc_C)
Type: Domain

The PAS (Per, Arnt, Sim) domain is an approximately 300 amino-acid segment of sequence similarity which is conserved between the Drosophila protein period clock (PER), the Ah receptor nuclear translocator (ARNT) and the Drosophila single-minded (SIM). It is composed of two or more imperfect repeats (PAS-1, PAS-2). In addition, some proteins have another similar region of 40-45 amino acids situated carboxy-terminal to any PAS repeat and which contributes to the PAS structural domain: the PAC motif. The PAS family can be divided in two groups; the proteins that have the PAS motif followed by a PAC motif, and those that do not. It appears that these domains are directly linked, and that together they form the conserved 3D PAS fold. The division between the PAS and PAC domains is caused by major differences in sequences in the region connecting these two motifs . Within the bHLH/PAS proteins, the PAS domain is involved in protein dimerization with another protein of the family. It has also been associated with light reception, light regulation and circadian rhythm regulators (clock).

In bacteria, the PAS domain is usually associated with the input domain of a histidine kinase, or a sensor protein that regulates a histidine kinase.
Succinate dehydrogenase/fumarate reductase type B, transmembrane subunit (SuccDH_FuR_B_TM-su)
Type: Family

Succinate dehydrogenase (SDH) is a membrane-bound complex of two main components: a membrane-extrinsic component composed of an FAD-binding flavoprotein and an iron-sulphur protein, and a hydrophobic component composed of a cytochrome b and a membrane anchor protein. The cytochrome b component is a mono-haem transmembrane protein belonging to a family that includes:

Cytochrome b-556 from bacterial SDH (gene sdhC).

Cytochrome b560 from the mammalian mitochondrial SDH complex, which is encoded in the mitochondrial genome of some algae and in the plant Marchantia polymorpha.

Cytochrome b from yeast mitochondrial SDH complex (gene SDH3 or CYB3).

Protein cyt-1 from Caenorhabditis elegans.

These cytochromes are proteins of about 130 residues that comprise three transmembrane regions. There are two conserved histidines which may be involved in binding the haem group.

This family also includes the subunit C (the cytochrome B subunit) of type B fumarate reductases .
Large ribosomal subunit protein uL6-like (Ribosomal_uL6-like)
Type: Family

Large ribosomal subunit protein uL6 was previously known as L6. In Escherichia coli, it is located in the aminoacyl-tRNA binding site of the peptidyltransferase centre, and is known to bind directly to 23S rRNA. It belongs to a family of ribosomal proteins, including L6 from bacteria, cyanelles (structures that perform similar functions to chloroplasts, but have structural and biochemical characteristics of Cyanobacteria) and mitochondria; and L9 from mammals, Drosophila, plants and yeast. L6 contains two domains with almost identical folds, suggesting that is was derived by the duplication of an ancient RNA-binding protein gene. Analysis reveals several sites on the protein surface where interactions with other ribosome components may occur, the N terminus being involved in protein-protein interactions and the C terminus containing possible RNA-binding sites .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Casein kinase II, regulatory subunit (Casein_kinase_II_reg-sub)
Type: Family

Casein kinase, a ubiquitous well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Ser or Thr in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha-and 2 beta-subunits . However, some species (e.g., mammals) possess 2 related forms of the alpha-subunit (alpha and alpha'), while others (e.g., fungi) possess 2 related beta-subunits (beta and beta') .
Galactokinase (Galactokinase)
Type: Family

Galactokinase catalyses the first reaction in the galactose metabolism pathway, the ATP-dependent phosphorylation of galactose, yielding galactose-1-phosphate . Deficiency in this enzyme results in the disease galactosemia, which is responsible for the formation of cataracts in newborn babies, and is possibly responsible for presenile cataracts in adults . In yeast, the GAL3 gene product is required for the GAL4-mediated induction of other enzymes involved in galactose metabolism. The induction of GAL1 production then reinforces this process, increasing the expression of other galactose-inducible genes. GAL3 has been shown to be similar to the GAL1 protein .
Prostanoid EP1 receptor (Prostglndn_EP1_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, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. 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.

EP1 receptors mediate contraction of gastrointestinal smooth muscles in various species, and relaxation of airway and uterine smooth muscles, especially in rodents. The receptors activate the phosphoinositide pathway via a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
Leu/Ile/Val-binding protein (Leu_Ile_Val-bd)
Type: Family

Leu/Ile/Val/Thr- and Leu-binding proteins, which share a high degree of sequence similarity, are components of the leucine-specific transport system. This is one of two periplasmic binding protein-dependent systems in the high-affinity transport of branched-chain amino acids in bacteria
. A much weaker sequence relationship has been reported between the periplasmic binding proteins and the aliphatic amidase expression-regulating protein, AmiC. On this basis, it has been suggested that AmiC may be capable of adopting a similar 3D fold .
Peptidase S6, IgA endopeptidase (Peptidase_S6)
Type: Family

This family consists of immunoglobulin A1 protease proteins. The immunoglobulin A1 protease cleaves immunoglobulin IgA and is found in pathogenic bacteria such as Neisseria gonorrhoeae . Not all of the members of this family are IgA proteases. EspP (

) from Escherichia coli O157:H7 cleaves human coagulation factor V and

is a hemoglobin protease from E. coli EB1 . This group of serine peptidases belong to the MEROPS peptidase family S6 (clan PA(S)).