SII-SWORD/CoKE huggingface dataset:
Transcription factor IIS, N-terminal (TFIIS_N)
Type: Domain

Transcription factor IIS (TFIIS) is a transcription elongation factor that increases the overall transcription rate of RNA polymerase II by reactivating transcription elongation complexes that have arrested transcription. The three structural domains of TFIIS are conserved from yeast to human. The 80 or so N-terminal residues form a protein interaction domain containing a conserved motif, which has been called the LW motif because of the invariant leucine and tryptophan residues it contains. This N-terminal domain is not required for transcriptional activity, and while a similar sequence has been identified in other transcription factors, and proteins that are predominantly nuclear localized , the domain is also found in proteins not directly involved in transcription. This domain is found in (amongst others):

MED26 (also known as CRSP70 and ARC70), a subunit of the Mediator complex, which is required for the activity of the enhancer-binding protein Sp1.

Elongin A, a subunit of a transcription elongation factor previously known as SIII. It increases the rate of transcription by suppressing transient pausing of the elongation complex.

PPP1R10, a nuclear regulatory subunit of protein phosphatase 1 that was previously known as p99, FB19 or PNUTS.

IWS1, which is thought to function in both transcription initiation and elongation.

The TFIIS N-terminal domain is a compact four-helix bundle. The hydrophobic core residues of helices 2, 3, and 4 are well conserved among TFIIS domains, although helix 1 is less conserved .
RNA-binding protein YhbY (RNA-binding_YhbY)
Type: Family

The YhbY family of proteins are predicted to bind RNA on the basis of structural similarity to known RNA-binding proteins . The Escherichia coli YhbY protein cosediments with free 50S ribosomal subunits, implying a role in ribosome assembly.
Dihydrofolate reductase conserved site (DHFR_CS)
Type: Conserved_site

Dihydrofolate reductase (DHFR) (

) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in
de novo
synthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) , and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood .

Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar . The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself .

This entry covers the region in the N-terminal part of the DHFR domain, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme .
FAD-binding domain, ferredoxin reductase-type (FAD-bd_FR_type)
Type: Domain

Flavoenzymes have the ability to catalyse a wide range of biochemical reactions. They are involved in the dehydrogenation of a variety of metabolites, in electron transfer from and to redox centres, in light emission, in the activation of oxygen for oxidation and hydroxylation reactions . About 1% of all eukaryotic and prokaryotic proteins are predicted to encode a flavin adenine dinucleotide (FAD)-binding domain .

According to structural similarities and conserved sequence motifs, FAD-binding domains have been grouped in three main families: (i)the ferredoxin reductase (FR)-type FAD-binding domain, (ii) the FAD-binding domains that adopt a Rossmann fold and (iii) the PCMH-type FAD-binding domain .

The FAD cofactor consists of adenosine monophosphate (AMP) linked to flavin mononucleotide (FMN) by a pyrophosphate bond. The AMP moiety is composed of the adenine ring bonded to a ribose that is linked to a phosphate group. The FMN moiety is composed of the isoalloxazine-flavin ring linked to a ribitol, which is connected to a phosphate group. The flavin functions mainly in a redox capacity, being able to take up two electrons from one substrate and release them two at a time to a substrate or coenzyme, or one at a time to an electron acceptor. The catalytic function of the FAD is concentrated in the isoalloxazine ring, whereas the ribityl phosphate and the AMP moiety mainly stabilise cofactor binding to protein residues .

The structural core of all FR family members is well conserved. The FAD-binding fold characteristic of the FR family is a cylindrical β-domain with a flattened six-stranded antiparallel β-barrel organised into two orthogonal sheets (B1-B2-B5 and B4-B3-B6) separated by one α-helix . The cylinder is open between strands B4 and B5 which makes space for the isoalloxazine and ribityl moieties of the FAD. One end of the cylinder is covered by the only helix of the domain, which is essential for the binding of the pyrophosphate groups of the FAD. The FR family contains two conserved motifs, one (R-x-Y-[ST]) located in B4 where the invariant positively charge Arg residue forms hydrogen bonds to the negative pyrophosphate oxygen atom. The other conserved sequence motif is G-x(2)-[ST]-x(2)-L-x(5)-G-x(7)-P-x-G, which is part of H1-B6 and is known as the phosphate-binding motif .
Myb domain (Myb_dom)
Type: Domain

The myb-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of approximately 55 amino acids, typically occurring in a tandem repeat in eukaryotic transcription factors. The domain is named after the retroviral oncogene v-myb, and its cellular counterpart c-myb, which encode nuclear DNA-binding proteins that specifically recognise the sequence YAAC(G/T)G . Myb proteins contain three tandem repeats of 51 to 53 amino acids, termed R1, R2 and R3. This repeat region is involved in DNA-binding and R2 and R3 bind directly to the DNA major groove. The major part of the first repeat is missing in retroviral v-Myb sequences and in plant myb-related (R2R3) proteins . A single myb-type HTH DNA-binding domain occurs in TRF1 and TRF2.

The 3D-structure of the myb-type HTH domain forms three α-helices . The second and third helices connected via a turn comprise the helix-turn-helix motif. Helix 3 is termed the recognition helix as it binds the DNA major groove, like in other HTHs.
Glutamine amidotransferase type 2 domain (GATase_2_dom)
Type: Domain

A large group of biosynthetic enzymes are able to catalyse the removal of the ammonia group from glutamine and then to transfer this group to a substrate to form a new carbon-nitrogen group. This catalytic activity is known as glutamine amidotransferase (GATase) . The GATase domain exists either as a separate polypeptidic subunit or as part of a larger polypeptide fused in different ways to a synthase domain. On the basis of sequence similarities two classes of GATase domains have been identified : class-I (also known as trpG-type or triad) and class-II (also known as purF-type or Ntn). Class-II (or type 2) GATase domains have been found in the following enzymes:

Amido phosphoribosyltransferase (glutamine phosphoribosylpyrophosphate amidotransferase). An enzyme which catalyses the first step in purine biosynthesis, the transfer of the ammonia group of glutamine to PRPP to form 5-phosphoribosylamine (gene purF in bacteria, ADE4 in yeast).

Glucosamine--fructose-6-phosphate aminotransferase. This enzyme catalyses a key reaction in amino sugar synthesis, the formation of glucosamine 6-phosphate from fructose 6-phosphate and glutamine (gene glmS in Escherichia coli, nodM in Rhizobium, GFA1 in yeast).

Asparagine synthetase (glutamine-hydrolyzing). This enzyme is responsible for the synthesis of asparagine from aspartate and glutamine.

Glutamate synthase (gltS), an enzyme which participates in the ammonia assimilation process by catalysing the formation of glutamate from glutamine and 2-oxoglutarate. Glutamate synthase is a multicomponent iron-sulphur flavoprotein and three types occur which use a different electron donor: NADPH-dependent gltS (large chain), ferredoxin-dependent gltS and NADH-dependent gltS .

The active site is formed by a cysteine present at the N-terminal extremity of the mature form of all these enzymes . Two other conserved residues, Asn and Gly, form an oxyanion hole for stabilisation of the formed tetrahedral intermediate. An insert of ~120 residues can occur between the conserved regions . In some class-II GATases (for example in Bacillus subtilis or chicken amido phosphoribosyltransferase) the enzyme is synthesised with a short propeptide which is cleaved off post-translationally by a proposed autocatalytic mechanism. Nuclear-encoded Fd-dependent gltS have a longer propeptide which may contain a chloroplast-targeting peptide in addition to the propeptide that is excised on enzyme activation.

The 3-D structure of the GATase type 2 domain forms a four layer α/β/β/α architecture which consists of a fold similar to the N-terminal nucleophile (Ntn) hydrolases. These have the capacity for nucleophilic attack and the possibility of autocatalytic processing. The N-terminal position and the folding of the catalytic Cys differ strongly from the Cys-His-Glu triad which forms the active site of GATases of type 1.
Riboflavin synthase-like beta-barrel (Riboflavin_synthase-like_b-brl)
Type: Homologous_superfamily

This superfamily represents a structural domain with a closed β-barrel fold with greek-key topology. Domains with this structure can be found in the following proteins:

Riboflavin synthase, which contains two homologous domains of this structure .

The FAD-binding (N-terminal) domain of ferredoxin reductase (flavodoxin reductase), where the FAD-binding domain is coupled with a NADP-binding domain of the α/β class .

The FAD-binding domain of NADPH-cytochrome p450 reductase; however, this domain has an additional α-helical domain inserted into it .

Riboflavin synthase (

) catalyses the final step in the biosynthesis of vitamin B2, namely the dismutation of two molecules of 6,7-dimethyl-8-ribityllumazine to yield riboflavin and 4-(1-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine (which is recycled) .

Flavins can act as primary and secondary emitters in bacterial luminescence. Lumazine proteins are involved in the bioluminescence of certain marine bacteria. These proteins are catalytically inactive, but they resemble riboflavin synthase . Lumazine is non-covalently bound to the fluorophore 6,7-dimethyl-8-ribityllumazine, which is the substrate of riboflavin synthase.

Ferredoxin reductase is a FAD-containing oxidoreductase that transports electrons between flavodoxin or ferredoxin and NADPH. In Escherichia coli, ferredoxin reductase together with flavodoxin is involved in the reductive activation of three enzymes: cobalamin-dependent methionine synthase, pyruvate formate lyase and anaerobic ribonucleotide reductase . An additional function for the oxidoreductase appears to be to protect the bacteria against oxygen radicals. The β-barrel domain found in ferredoxin reductase is similar to that found in: NAD(P)H:flavin oxidoreductase , the core domain of nitrate reductase , cytochrome b5 reductase , phthalate dioxygenase reductase (which contains an additional 2Fe-2S ferredoxin domain) , benzoate dioxygenase reductase , the PyrK subunit of dihydroorotate dehydrogenase B , the central domain of flavohaemoglobin (which contains an additional globin domain) , and methane monooxygenase component C (MmoC) .
Gamma-glutamylcyclotransferase (G-Glutamylcylcotransferase)
Type: Family

This entry contains the human protein C7orf24 (

) which has been used as a cancer marker with a potential role in cell proliferation. It has been characterised as gamma-glutamyl cyclotransferase (GGCT), a homodimer of two 21kDa subunits, that catalyses the formation of 5-oxoproline (2-pyrrolidone-5-carboxylic acid, pyroglutamic acid) from gamma-glutamyl dipeptides (

) .

L-gamma-glutamyl-L-amino acid -> 5-oxoproline + L-amino acid

The structure of GGCT has been solved. Its topology is unrelated to other enzymes associated with cyclotransferase-like activity and its structure has been termed the GGCT-fold, which appears to be related to the BtrG-like superfamily. A potential active site pocket contains a highly conserved glutamic acid (Glu(98)), which when converted to either Ala or Gln completely inactivates the enzyme without altering the overall fold .

This entry also includes GGCT gliK, GGCT aclK and GGCT verK from fungi. GGCT gliK is part of the gene cluster that mediates the biosynthesis of gliotoxin, a member of the epipolythiodioxopiperazine (ETP) class of toxins characterised by a disulfide bridged cyclic dipeptide . GGCT aclK mediates the biosynthesis of aspirochlorine . GGCT verK mediates the biosynthesis of 11'-deoxyverticillin A, one of the dimeric epipolythiodioxopiperazines (ETPs) from the verticillin family that act as mycotoxins .
Rieske [2Fe-2S] iron-sulphur domain (Rieske_2Fe-2S)
Type: Domain

This entry represents the Rieske [2Fe-2S] iron-sulphur domain. The structure of several Rieske domains has been solved . It contains three layers of antiparallel β-sheets forming two β-sandwiches. Both β-sandwiches share the central sheet 2. The metal-binding site is at the top of the β-sandwich formed by the sheets 2 and 3. The Fe1 iron of the Rieske cluster is coordinated by two cysteines while the other iron Fe2 is coordinated by two histidines. Two inorganic sulphide ions bridge the two iron ions forming a flat, rhombic cluster.

Iron-sulphur clusters are grouped into three main categories based on their atomic content: [2Fe-2S], [3Fe-4S], [4Fe-4S] (see

), and other hybrid or mixed metal types. Two general types of [2Fe-2S] clusters are known and they differ in their coordinating residues. The ferredoxin-type [2Fe-2S] clusters are coordinated to the protein by four cysteine residues (see

). The Rieske-type [2Fe-2S] cluster is coordinated to its protein by two cysteine residues and two histidine residues .

Rieske-type iron-sulphur clusters are common to electron transfer chains of mitochondria and chloroplast and to non-heme iron oxygenase systems:

The Rieske protein of the Ubiquinol-cytochrome c reductase (

) (also known as the bc1 complex or complex III), a complex of the electron transport chains of mitochondria and of some aerobic prokaryotes; it catalyses the oxidoreduction of ubiquinol and cytochrome c.

The Rieske protein of chloroplastic plastoquinone-plastocyanin reductase (

) (also known as the b6f complex). It is functionally similar to the bc1 complex and catalyses the oxidoreduction of plastoquinol and cytochrome f.

Bacterial naphthalene 1,2-dioxygenase subunit alpha, a component of the naphthalene dioxygenase (NDO) multicomponent enzyme system which catalyses the incorporation of both atoms of molecular oxygen into naphthalene to form cis-naphthalene dihydrodiol.

Bacterial 3-phenylpropionate dioxygenase ferredoxin subunit.

Bacterial toluene monooxygenase.

Bacterial biphenyl dioxygenase.
Lipid-binding serum glycoprotein, N-terminal (Lipid-bd_serum_glycop_N)
Type: Domain

This entry represents the N-terminal domain found in several lipid-binding serum glycoproteins. The N- and C-terminal domains share a similar two-layer α/β structure, but they show little sequence identity. Proteins containing this N-terminal domain include:

Bactericidal permeability-increasing protein (BPI)

Lipopolysaccharide-binding protein (LBP)

Cholesteryl ester transfer protein (CETP)

Phospholipid transfer protein (PLTP)

Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)

Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria . BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity .
Bactericidal permeability-increasing protein, alpha/beta domain superfamily (Bactericidal_perm-incr_a/b_dom)
Type: Homologous_superfamily

This superfamily represents a structural domain with a core structure consisting of two layers, alpha/beta. These homologous structural domains can show little sequence identity with each other. A number of mammalian lipid-binding serum glycoproteins contain one or more such structural domains, including:

Bactericidal permeability-increasing protein (BPI)

Lipopolysaccharide-binding protein (LBP)

Cholesteryl ester transfer protein (CETP)

Phospholipid transfer protein (PLTP)

Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)

Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria . BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity .
KaiA/RbsU helical domain superfamily (KaiA/RbsU_helical_domain_sf)
Type: Homologous_superfamily

This superfamily represents a structural domain consisting of four helices in a bundle with a right-handed superhelix. Homologous structural domains can be found in:

The C-terminal domain of the circadian clock protein KaiA

The N-terminal domain of the phosphoserine phosphatase protein RsbU

The cyanobacterial clock proteins KaiA, KaiB and KaiC are proposed as regulators of the circadian rhythm in cyanobacteria. KaiA activates the expression of the kaiBC locus, while KaiC represses it. KaiA is composed of three functional domains: the N-terminal amplitude-amplifier domain, the central period-adjuster domain and the C-terminal clock-oscillator domain. The C-terminal domain is responsible for dimer formation, binding to KaiC, enhancing KaiC phosphorylation and generating the circadian oscillations . The KaiA protein from Anabaena sp. (strain PCC 7120) lacks the N-terminal CheY-like domain.

The phosphoserine phosphatase RsbU acts as a positive regulator of the general stress-response factor of Gram-positive organisms, sigma-B. RsbU dephosphorylates rsbV in response to environmental stress conveyed from the rsbXST module. The phosphatase activity of RsbU is stimulated during the stress response by associating with the RsbT kinase. This association leads to the induction of sigmaB activity. The N-terminal domain forms a helix-swapped dimer that is otherwise similar to the KaiA domain dimer. Deletions in the N-terminal domain are deleterious to the activity of RsbU. The C-terminal domain of RsbU is similar to the catalytic domains of PP2C-type phosphatases .
DHBP synthase RibB-like alpha/beta domain superfamily (DHBP_synth_RibB-like_a/b_dom)
Type: Homologous_superfamily

This superfamily represents a structural domain consisting of segregated alpha and beta regions in 3-layers. Homologous domains with this structure are found in:

3,4-dihydroxy-2-butanone 4-phosphate synthase (

) (DHBP synthase) (RibB)

A family of eukaryotic and prokaryotic hypothetical proteins that includes YrdC and YciO from Escherichia coli and MTH1692 from the archaea Methanothermobacter thermautotrophicus (Methanobacterium thermoformicicum)

DHBP synthase RibB catalyses the conversion of D-ribulose 5-phosphate to formate and 3,4-dihydroxy-2-butanone 4-phosphate, the latter serving as the biosynthetic precursor for the xylene ring of riboflavin . In Photobacterium leiognathi, the riboflavin synthesis genes ribB (DHBP synthase), ribE (riboflavin synthase), ribH (lumazone synthase) and ribA (GTP cyclohydrolase II) all reside in the lux operon . RibB is sometimes found as a bifunctional enzyme with GTP cyclohydrolase II that catalyses the first committed step in the biosynthesis of riboflavin (

). No sequences with significant homology to DHBP synthase are found in the metazoa.

The YrdC family of hypothetical proteins are widely distributed in eukaryotes and prokaryotes and occur as: (i) independent proteins, (ii) with C-terminal extensions, and (iii) as domains in larger proteins, some of which are implicated in regulation . YrdC from Escherichia coli preferentially binds to double-stranded RNA and DNA. YrdC is predicted to be an rRNA maturation factor, as deletions in its gene lead to immature ribosomal 30S subunits and, consequently, fewer translating ribosomes . Therefore, YrdC may function by keeping an rRNA structure needed for proper processing of 16S rRNA, especially at lower temperatures. Threonylcarbamoyl-AMP synthase (Sua5) is an example of a multi-domain protein that contains an N-terminal YrdC-like domain and a C-terminal Sua5 domain. Sua5 was identified in Saccharomyces cerevisiae (Baker's yeast) as a suppressor of a translation initiation defect in the cytochrome c gene and is required for formation of a threonylcarbamoyl group on adenosine at position 37 in tRNAs . HypF is involved in the synthesis of the active site of [NiFe]-hydrogenases .
PLC-like phosphodiesterase, TIM beta/alpha-barrel domain superfamily (PLC-like_Pdiesterase_TIM-brl)
Type: Homologous_superfamily

This superfamily represents a structural domain consisting of a TIM β/α-barrel. These domains are found in several phospholipase C (PLC) like phosphodiesterases, including:

Mammalian phospholipase C isozyme D1 .

Bacterial phosphatidylinositol-specific phospholipase C .

Glycerophosphodiester phosphodiesterases, such as GlpQ from Escherichia coli and UgpQ from Agrobacterium tumefaciens .

Phospholipase C (PLC) isozymes are directly activated by heterotrimeric G proteins and Ras-like GTPases to hydrolyse phosphatidylinositol 4,5-bisphosphate into the second messengers diacylglycerol and inositol 1,4,5-trisphosphate. PLC enzymes often play central roles in various signalling cascades .
Aryldialkylphosphatase, zinc-binding site (AryldialkylPase_Zn-BS)
Type: Binding_site

Synonym(s): Paraoxonase, A-esterase, Aryltriphosphatase, Phosphotriesterase, Paraoxon hydrolase

Bacteria such as Brevundimonas diminuta (Pseudomonas diminuta) harbour a plasmid that carries the gene for aryldialkylphosphatase (

) (PTE) (also known as parathion hydrolase). This enzyme has attracted interest because of its potential use in the detoxification of chemical waste and warfare agents and its ability to degrade agricultural pesticides such as parathion. It acts specifically on synthetic organophosphate triesters and phosphorofluoridates. It does not seem to have a naturally occuring substrate and may thus have optimally evolved for utilizing paraoxon.

Aryldialkylphosphatase belongs to a family of enzymes that possess a binuclear zinc metal centre at their active site. The two zinc ions are coordinated by six different residues, six of which being histidines. This family so far includes, in addition to the parathion hydrolase, the following proteins:

Escherichia coli protein Php, the substrate of which is not yet known.

Mycobacterium tuberculosis phosphotriesterase homology protein Rv0230C.

Mammalian phosphotriesterase related protein (PTER) (RPR-1).

This entry corresponds to the region located in the N-terminal section that contains two histidines that bind the first of the two zinc ions.