SII-SWORD/CoKE huggingface dataset:
Mannitol dehydrogenase, N-terminal (Mannitol_DH_N)
Type: Domain

Mannitol-1-phosphate 5-dehydrogenase catalyses the NAD-dependent reduction of mannitol-1-phosphate to fructose-6-phosphate as part of the phosphoenolpyruvate-dependent phosphotransferase system (PTS). The PTS facilitates the vectorial translocation of metabolisable carbohydrates to form the corresponding sugar phosphates, which are then converted to glycolytic intermediates . Mannitol 2-dehydrogenase catalyses the NAD-dependent reduction of mannitol to fructose . Several dehydrogenases have been shown to be evolutionary related, including mannitol-1-phosphate 5-dehydrogenase (

) (gene mtlD), mannitol 2-dehydrogenase (

) (gene mtlK); mannonate oxidoreductase (

) (fructuronate reductase) (gene uxuB); Escherichia coli hypothetical proteins ydfI and yeiQ; and yeast hypothetical protein YEL070w. This domain has a Rossmann-type fold.
PseI/NeuA/B-like (PseI/NeuA/B-like_N)
Type: Domain

This entry represents the N-terminal TIM-barrel domain found in a number of proteins including NeuB, SpsE, PseI and homologues.

NeuB is the prokaryotic N-acetylneuraminic acid synthase. It catalyses the direct formation of N-acetylneuraminic acid (Neu5Ac), the most common sialic acid, by condensation of phosphoenolpyruvate (PEP) and N-acetylmannosamine (ManNAc). Mammals synthesise the 9-phosphate form, Neu5Ac-9-P, and utilise ManNAc-6-P instead of ManNAc . The bacterial and mammalian enzymes share 30%-40% sequence identity and are composed of two distinct domains. The N-terminal domain (NeuB domain,

) consists of ~250 amino acid residues, and is considered to bind the sugar substrates. The C-terminal domain consists of ~75 amino acid residues, and is called the antifreeze-like (AFL) domain, since it is similar to those observed in a variety of functional type III antifreeze proteins (AFPs) .
RAD50, zinc hook (Zn_hook_RAD50)
Type: Domain

This entry represents the zinc hook of human DNA repair protein RAD50 and similar sequences found in all cellular organisms. Dimerisation at this domain is critical for the function of the Mre11 complex .

The MRN complex (Mre11-Rad50-Nbs1) plays an important role in many DNA metabolic events that involve DNA double-stranded breaks. MRN is one of the first factors to be localised to DNA lesions where it might have a structural role by tethering and stabilising broken chromosomes .

Rad50 is a split ABC-type ATPase; its centre contains a long heptad repeat that folds into an antiparallel coiled coil, bringing the N-terminal (Walker A) and the C-terminal (Walker B) domains in close proximity . The apex of the coiled coil contains a dimerisation interface, a conserved Cys-X-X-Cys motif in a hook-shaped domain that dimerises with a second hook domain via cysteine-mediated zinc ion coordination. This zinc dependent dimerisation event allows the formation of a complex that has appropriate lengths and conformational properties to link sister chromatids in homologous recombination and DNA ends in non-homologous end-joining.
Vitelline membrane cysteine-rich domain (Vitelline_membr_Cys-rich-dom)
Type: Domain

In Drosophila melanogaster (Fruit fly) the vitelline membrane (VM) is the first layer of the eggshell produced by the follicular epithelium. It is composed of at least four different proteins. VM proteins are similarly organised with a central highly conserved 38-amino acid domain which is flanked by unrelated regions. Since the surrounding regions have diverged significantly, it is possible that the VM domain is of key importance in VM protein structure . The VM domain contains three highly conserved cysteines.
WSTF/Acf1/Cbp146 (WSTF_Acf1_Cbp146)
Type: Domain

ACF (for ATP-utilising chromatin assembly and remodeling factor) is a chromatin-remodeling complex that catalyzes the ATP-dependent assembly of periodic nucleosome arrays. This reaction utilises the energy of ATP hydrolysis by ISWI, the smaller of the two subunits of ACF. Acf1, the large subunit of ACF, is essential for the full activity of the complex. The WAC (WSTF/Acf1/cbp146) domain is an ~110-residue module present at the N-termini of Acf1-related proteins in a variety of organisms. It is found in association with other domains such as the bromodomain, the PHD-type zinc finger, DDT or WAKS. The DNA-binding region of Acf1 includes the WAC domain, which is necessary for the efficient binding of ACF complex to DNA. It seems probable that the WAC domain will be involved in DNA binding in other related factors .
Zinc finger, TFIIB-type (Znf_TFIIB)
Type: Domain

This entry represents a zinc finger motif found in transcription factor IIB (TFIIB). In eukaryotes the initiation of transcription of protein encoding genes by the polymerase II complexe (Pol II) is modulated by general and specific transcription factors. The general transcription factors operate through common promoters elements (such as the TATA box). At least seven different proteins associate to form the general transcription factors: TFIIA, -IIB, -IID, -IIE, -IIF, -IIG, and -IIH .

TFIIB and TFIID are responsible for promoter recognition and interaction with pol II; together with Pol II, they form a minimal initiation complex capable of transcription under certain conditions. The TATA box of a Pol II promoter is bound in the initiation complex by the TBP subunit of TFIID, which bends the DNA around the C-terminal domain of TFIIB whereas the N-terminal zinc finger of TFIIB interacts with Pol II .

The TFIIB zinc finger adopts a zinc ribbon fold characterised by two β-hairpins forming two structurally similar zinc-binding sub-sites . The zinc finger contacts the rbp1 subunit of Pol II through its dock domain, a conserved region of about 70 amino acids located close to the polymerase active site . In the Pol II complex this surface is located near the RNA exit groove. Interestingly this sequence is best conserved in the three polymerases that utilise a TFIIB-like general transcription factor (Pol II, Pol III, and archaeal RNA polymerase) but not in Pol I .

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.
Omega-atracotoxin, conserved site-2 (Omega_atracotoxin_CS2)
Type: Conserved_site

Omega-atracotoxins (ACTX) form a family of neurotoxins that block insect but not vertebrate voltage-gated calcium channels. Omega-ACTXs are environmentally benign, insect-specific toxins that represent excellent leads for the development of new pesticides. Omega-ACTXs comprise a disulphide-rich region that has a [C-C-CC-C-C] arrangement and possess a Knottin scaffold .
Huwentoxin, conserved site-1 (Huwentoxin_CS1)
Type: Conserved_site

The spider venoms often contain many active peptides such as neurotoxins, lectins, inhibitors to enzyme, etc. These peptides are very important for the spider's hunting and defending. During the long history of spider evolution, the peptides evolved into different structures and functions. Despite their different biological functions the following peptides appear to have evolved from the same ancestors and belong to the huwentoxin-1 family :

Ornithoctonus huwena (Chinese bird spider) (Selenocosmia huwena) huwentoxin-I (HWTX-I), a 33 amino acid peptide, which can block the N-type high-voltage activated calcium channels .

O. huwena (Chinese bird spider) (Selenocosmia huwena) huwentoxin-IIIa (HWTX-IIIa).

O. huwena (Chinese bird spider) (Selenocosmia huwena) huwentoxin-IV (HWTX-IV), a 35 amino acid peptide, which is an inhibitor of tetrodotoxin (TTX) sensitive voltage-gated sodium channel .

O. huwena (Chinese bird spider) (Selenocosmia huwena) huwentoxin-V (HWTX-V), a 35 amino acid insecticidal toxin which can reversibly paralyze in insects .

O. huwena (Chinese bird spider) (Selenocosmia huwena) huwenlectin-I (SHL-I), a 32 amino acid peptide with haemagglutination activity but almost no neurotoxin activity.

Selenocosmia hainana (Chinese bird spider) Hainantoxin-I (HNTX-I), Hainantoxin-III (HNTX-III), Hainantoxin-IV (HNTX-IV) and Hainantoxin-V (HNTX-V) .

Brachypelma smithii (Mexican red knee tarantula) Venom protein 5.

Grammostola rosea (Chilean rose tarantula) (Grammostola spatulata) voltage sensor toxin 1.

Peptides of the huwentoxin type I family contain 6 cysteine residues involved in three disulphide bonds. The three disulphide bridges have been assigned as C1-C4, C2-C5 and C3-C6. HWTX-I adopts a compact structure consisting of a small triple-stranded antiparallel β-sheet and five β-turns.
Conotoxin-I, conserved site (Conotoxin-I_CS)
Type: Conserved_site

This entry represents a conserved region characteristic of the I-superfamily of conotoxins.

Cone snail toxins, conotoxins, are small peptides with disulphide connectivity, that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulphide bonds and biological activities, conotoxins can be classified into several families . Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulphide through disulphide knot, in which the III-VI disulphide bond crosses the macrocycle formed by two other disulphide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N terminus; for further information see the KNOTTIN database (https://www.dsimb.inserm.fr/KNOTTIN/).

Conotoxins represent a unique arsenal of neuropharmacologically active peptides that have been evolutionarily tailored to afford unprecedented and exquisite selectivity for a wide variety of ion-channel subtypes. The toxins derived from cone snails are currently being investigated for the treatment of chronic pain, epilepsy, cardiovascular diseases, psychiatric and movement disorders, spasticity, cancer, stroke as well as an anesthetic agent. Several potential analgesic and anti-inflammatory peptides from conotoxin families have been identified and patented , e.g. Conus magus (Magus cone) (Magician's cone snail) omega-conotoxin MVIIa (Ziconotide), which is used for the treatment of chronic pain, Conus catus (Cat cone) omega-conotoxin CVID, which is tested for treating severe morphine-resistant pain stress, and Conus geographus (Geography cone) (Nubecula geographus) omega-conotoxin GVIA, which may exert antagonistic effects against beta-endorphin induced anti-nociception.

The disulphide bonding network as well as specific amino acids in inter-cysteine loops provide specificity of conotoxins . The cysteine arrangement [C-C-CC-C-C] is the same for omega and delta families, which belong to the O-superfamily. The omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels . The M-superfamily Mu conotoxins have two types of cysteine arrangement [CC-C-C-CC] and [CC-C-C-C-C], but knottin scaffold is not observed. Mu conotoxins target the voltage-gated sodium channels and are useful probes for investigating voltage-dependent sodium channels of excitable tissues . Alpha conotoxins belong to the A-superfamily and have two types of cysteine arrangement [CC-C-C] and [CCC-C-C-C] . Alpha conotoxins are competitive nicotinic acetylcholine receptor antagonists. The I-superfamily of conotoxins is characterised by a pattern of eight cysteine residues that form four disulphide bridges. The arrangement of cysteine residues is similar to the Janus-faced atracotoxin peptides characterised from spider venoms .
CRA domain (CRA_dom)
Type: Domain

This entry represents the CRA (or CT11-RanBPM) domain, which is a protein-protein interaction domain present in crown eukaryotes (plants, animals, fungi) and which is found in Ran-binding proteins such as Ran-binding protein 9 (RanBP9 or RanBPM) and RanBP10. RanBPM is a scaffolding protein important in regulating cellular function in both the immune system and the nervous system, and may act as an adapter protein to couple membrane receptors to intracellular signaling pathways. This domain is at the C terminus of the proteins and is the binding domain for the CRA motif, which is comprised of approximately 100 amino acids at the C-terminal of RanBPM. It was found to be important for the interaction of RanBPM with Fragile X messenger ribonucleoprotein 1 (FMRP/FMR1), but its functional significance has yet to be determined .
LEM-like domain (LEM-like_dom)
Type: Domain

The LEM (LAP2, emerin, MAN1) domain is a globular module of approximately 40 amino acids, which is mostly found in the nucleoplasmic portions of metazoan inner nuclear membrane proteins. The LEM domain has been shown to mediate binding to BAF (barrier-to-autointegration factor) and BAF-DNA complexes.
CD47-like, transmembrane (CD47-like_TM)
Type: Domain

This entry represents the transmembrane region found at the C-terminal end of Leukocyte surface antigen CD47 proteins from chordates and CD47-like proteins A38, also known as Protein OPG166, from Poxvirus.

Human CD47 is an adhesive protein that mediates cell-to-cell interactions . It is involved in signal transduction, cardiovascular homeostasis, inflammation, apoptosis, angiogenesis, cellular self-renewal, and immunoregulation .

OPG166 from Vaccinia virus promotes, when overexpressed, the influx of extracellular Ca2 , leading to membrane permeability and host cell necrosis .
Glycosyl hydrolase family 32, N-terminal (Glyco_hydro_32_N)
Type: Domain

This domain corresponds to the N-terminal domain of glycosyl transferase family 32 which forms a five bladed β propeller structure .
Alcohol dehydrogenase-like, C-terminal (ADH-like_C)
Type: Domain

This entry represents the cofactor-binding domain in alcohol dehydrogenases, which is normally found towards the C-terminal. Structural studies indicate that it forms a classical Rossman fold that reversibly binds NAD(H) . This entry also includes NADP-dependent quinone oxidoreductase (

), an enzyme found in bacteria (gene qor), in yeast and in mammals, where, in some species such as rodents, it has been recruited as an eye lens protein and is known as zeta-crystallin . The sequence of quinone oxidoreductase is distantly related to that of other zinc-containing alcohol dehydrogenases, and it lacks the zinc-ligand residues. The torpedo fish and mammalian synaptic vesicle membrane protein vat-1 is related to qor. Other related NADP-dependent oxidoreductases are represented by this entry, such as Enoyl-[acyl-carrier-protein], probable D-xylulose and Prostaglandin reductases.

Alcohol dehydrogenase (

) (ADH) catalyses the reversible oxidation of alcohols to their corresponding acetaldehyde or ketone with the concomitant reduction of NAD:

alcohol + NAD = aldehyde or ketone + NADH

Currently three structurally and catalytically different types of alcohol dehydrogenases are known:

Zinc-containing 'long-chain' alcohol dehydrogenases.

Insect-type, or 'short-chain' alcohol dehydrogenases.

Iron-containing alcohol dehydrogenases.

Zinc-containing ADH's are dimeric or tetrameric enzymes that bind two atoms of zinc per subunit. One of the zinc atoms is essential for catalytic activity while the other is not. Both zinc atoms are coordinated by either cysteine or histidine residues; the catalytic zinc is coordinated by two cysteines and one histidine. Zinc-containing ADH's are found in bacteria, mammals, plants, and in fungi. In many species there is more than one isozyme (for example, humans have at least six isozymes, yeast have three, etc.). A number of other zinc-dependent dehydrogenases are closely related to zinc ADH and are included in this family:

Sorbitol dehydrogenase (

)

L-threonine 3-dehydrogenase (

)

Glutathione-dependent formaldehyde dehydrogenase (

)

Mannitol dehydrogenase (

)
Transcription factor TFIIB, cyclin-like domain (TFIIB_cyclin)
Type: Domain

In eukaryotes, transcription initiation of all protein encoding genes involves the polymerase II system. This sytem is modulated by both general and specific transcription factors. The general factors (which include TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIG and TFIIH) operate through common promoter elements, such as the TATA box. Transcription factor IIB (TFIIB) is of central importance in transcription of class II genes. It associates with TFIID-TFIIA bound to DNA (the DA complex) to form a ternary TFIID-IIA-IBB (DAB) complex, which is recognised by RNA polymerase II . TFIIB comprises ~315-340 residues and contains an imperfect C-terminal repeat of a 75-residue domain that may contribute to the symmetry of the folded protein. The basal archaeal transcription machinery resembles that of the eukaryotic polymerase II system and includes a homologue of TFIIB .

This entry represents a cyclin-like domain which is found repeated in the C-terminal region of a variety of eukaryotic TFIIB's and their archaeal counterparts. These domains individually form the typical cyclin fold, and in the transcription complex they straddle the C-terminal region of the TATA-binding protein - an interaction essential for the formation of the transcription initiation complex .
Immunoglobulin-like beta-sandwich domain (Immunoglobulin_dom)
Type: Domain

This entry represents the immunoglobulin-like domain that is found in a number of proteins with diverse functions. Examples include T-cell surface glycoprotein CD4, Neurotrimin, Interleukin-1 receptor accessory protein-like 1, Receptor tyrosine kinases among others. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions.
Gastrin/cholecystokinin, conserved site (Gastrin/cholecystokinin_CS)
Type: Conserved_site

Gastrin and cholecystokinin (CCK) are structurally and functionally related peptide hormones that function as hormonal regulators of various digestive processes and feeding behaviours. They are known to induce gastric secretion, stimulate pancreatic secretion, increase blood circulation and water secretion in the stomach and intestine, and stimulate smooth muscle contraction. Originally found in the gut, these hormones have since been shown to be present in various parts of the nervous system. Like many other active peptides they are synthesized as larger protein precursors that are enzymatically converted to their mature forms. They are found in several molecular forms due to tissue-specific post-translational processing. A number of other peptides are known to belong to the same family:

Caerulein, an amphibian skin peptide, with a biological activity similar to that of CCK or gastrin. There are different types of caerulein in which a single or up to four copies of the peptide are present.

Leukosulfakinin I and II (LSK) are peptides, isolated from cockroach, that change the frequency and amplitude of contractions of the hindgut.

Drosulfakinins I and II are putative CCK-homologues from Drosophila. Those two peptides are part of a precursor sequence that was isolated using a probe based on the sequence of CCK and LSK.

A chicken antrum peptide which is a potent stimulus of avian gastric acid but not of pancreatic secretion.

Cionin , a neuropeptide from the protochordate Ciona intestinalis (Transparent sea squirt).

The biological activity of gastrin and CCK is associated with the last five C-terminal residues. One or two positions downstream, there is a conserved sulphated tyrosine residue.
PrkA, AAA domain (Prk_AAA)
Type: Domain

This entry represents the N-terminal AAA domain in PrkA proteins.

ATP-dependent protease PrkA proteins are bacterial and archaeal serine kinases, approximately 630 residues in length. They possesses the A-motif of nucleotide-binding proteins and exhibit distant homology to eukaryotic protein kinases .
Alcohol dehydrogenase-like, N-terminal (ADH-like_N)
Type: Domain

This is the catalytic domain of alcohol dehydrogenases. Many of them contain an inserted zinc-binding domain. This domain has a GroES-like structure, a name derived from the superfamily of proteins with a GroES fold. Proteins with a GroES fold structure have a highly conserved hydrophobic core and a glycyl-aspartate dipeptide which is thought to maintain the fold . This entry also includes NADP-dependent quinone oxidoreductase (

), an enzyme found in bacteria (gene qor), in yeast and in mammals, where, in some species such as rodents, it has been recruited as an eye lens protein and is known as zeta-crystallin . The sequence of quinone oxidoreductase is distantly related to that of other zinc-containing alcohol dehydrogenases, and it lacks the zinc-ligand residues. The torpedo fish and mammalian synaptic vesicle membrane protein vat-1 is related to qor. Other related NADP-dependent oxidoreductases are represented by this entry, such as Enoyl-[acyl-carrier-protein] and probable D-xylulose reductase.

Alcohol dehydrogenase (

) (ADH) catalyses the reversible oxidation of alcohols to their corresponding acetaldehyde or ketone with the concomitant reduction of NAD:

alcohol + NAD = aldehyde or ketone + NADH

Currently three structurally and catalytically different types of alcohol dehydrogenases are known:

Zinc-containing 'long-chain' alcohol dehydrogenases.

Insect-type, or 'short-chain' alcohol dehydrogenases.

Iron-containing alcohol dehydrogenases.

Zinc-containing ADH's are dimeric or tetrameric enzymes that bind two atoms of zinc per subunit. One of the zinc atoms is essential for catalytic activity while the other is not. Both zinc atoms are coordinated by either cysteine or histidine residues; the catalytic zinc is coordinated by two cysteines and one histidine. Zinc-containing ADH's are found in bacteria, mammals, plants, and in fungi. In many species there is more than one isozyme (for example, humans have at least six isozymes, yeast have three, etc.). A number of other zinc-dependent dehydrogenases are closely related to zinc ADH and are included in this family:

Sorbitol dehydrogenase (

)

L-threonine 3-dehydrogenase (

)

Glutathione-dependent formaldehyde dehydrogenase (

)

Mannitol dehydrogenase (

)