SII-SWORD/CoKE huggingface dataset:
Aspartate carbamoyltransferase regulatory subunit, C-terminal domain superfamily (Asp_carbatrfase_reg_C_sf)
Type: Homologous_superfamily

Aspartate carbamoyltransferase (aspartate transcarbamylase, ATCase)

is an allosteric enzyme that plays a central role in the regulation of the pyrimidine pathway in bacteria. The holoenzyme is a dodecamer composed of six catalytic chains, each with an active site, and six regulatory chains lacking catalytic activity . The catalytic subunits exist as a dimer of catalytic trimers, (c3)2, while the regulatory subunits exist as a trimer of regulatory dimers, (r2)3, therefore the complete holoenzyme can be represented as (c3)2(r2)3. The association of the catalytic subunits c3 with the regulatory subunits r2 is responsible for the establishment of positive co-operativity between catalytic sites for the binding of aspartate and it dictates the pattern of allosteric response toward nucleotide effectors. ATCase from Escherichia coli is the most extensively studied allosteric enzyme . The crystal structure of the T-state, the T-state with CTP bound, the R-state with N-phosphonacetyl-L-aspartate (PALA) bound, and the R-state with phosphonoacetamide plus malonate bound have been used in interpreting kinetic and mutational studies.

A high-resolution structure of E. coli ATCase in the presence of PALA (a bisubstrate analog) allows a detailed description of the binding at the active site of the enzyme and allows a detailed model of the tetrahedral intermediate to be constructed. The entire regulatory chain has been traced showing that the N-terminal regions of the regulatory chains R1 and R6 are located in close proximity to each other and to the regulatory site. This portion of the molecule may be involved in the observed asymmetry between the regulatory binding sites as well as in the heterotropic response of the enzyme . The C-terminal domain of the regulatory chains have a rubredoxin-like zinc-bound fold.

This entry represents the C-terminal domain superfamily.
Aspartate carbamoyltransferase regulatory subunit, N-terminal domain superfamily (Asp_carbatrfase_reg_N_sf)
Type: Homologous_superfamily

Aspartate carbamoyltransferase (aspartate transcarbamylase, ATCase)

is an allosteric enzyme that plays a central role in the regulation of the pyrimidine pathway in bacteria. The holoenzyme is a dodecamer composed of six catalytic chains, each with an active site, and six regulatory chains lacking catalytic activity . The catalytic subunits exist as a dimer of catalytic trimers, (c3)2, while the regulatory subunits exist as a trimer of regulatory dimers, (r2)3, therefore the complete holoenzyme can be represented as (c3)2(r2)3. The association of the catalytic subunits c3 with the regulatory subunits r2 is responsible for the establishment of positive co-operativity between catalytic sites for the binding of aspartate and it dictates the pattern of allosteric response toward nucleotide effectors. ATCase from Escherichia coli is the most extensively studied allosteric enzyme . The crystal structure of the T-state, the T-state with CTP bound, the R-state with N-phosphonacetyl-L-aspartate (PALA) bound, and the R-state with phosphonoacetamide plus malonate bound have been used in interpreting kinetic and mutational studies.

A high-resolution structure of E. coli ATCase in the presence of PALA (a bisubstrate analog) allows a detailed description of the binding at the active site of the enzyme and allows a detailed model of the tetrahedral intermediate to be constructed. The entire regulatory chain has been traced showing that the N-terminal regions of the regulatory chains R1 and R6 are located in close proximity to each other and to the regulatory site. This portion of the molecule may be involved in the observed asymmetry between the regulatory binding sites as well as in the heterotropic response of the enzyme . The C-terminal domain of the regulatory chains have a rubredoxin-like zinc-bound fold.

This entry represents the N-terminal domain superfamily. Structurally, this domain has a ferredoxin-like fold, which consists of an α+β sandwich with antiparallel β-sheet.
ATP synthase delta/epsilon subunit, C-terminal domain superfamily (ATP_F1_dsu/esu_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal long α-helix domain superfamily of ATPase subunits delta (in mitochondrial ATPase) or epsilon (in bacteria or chloroplast ATPase) .

The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) . In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP,

) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity .
Inosine monophosphate cyclohydrolase-like superfamily (IMP_cyclohydrolase-like_sf)
Type: Homologous_superfamily

This entry represents inosine monophosphate (IMP) cyclohydrolase superfamily, found in archaeal species, as well as some bacterial proteins of unknown function.

IMP cyclohydrolase catalyses the cyclisation of 5-formylamidoimidazole-4-carboxamide ribonucleotide to IMP, a reaction which is important in de novo purine biosynthesis in archaeal species . This single domain protein is arranged to form an overall fold that consists of a four-layered α-β-β-α core structure. The two antiparallel β-sheets pack against each other and are covered by α-helices on one face of the molecule. The protein is structurally similar to members of the N-terminal nucleophile (NTN) hydrolase superfamily. A deep pocket was in fact found on the surface of IMP cyclohydrolase in a position equivalent to that of active sites of NTN-hydrolases, but an N-terminal nucleophile could not be found. Therefore, it is thought that this enzyme is structurally but not functionally similar to members of the NTN-hydrolase family .

In bacteria this step is catalysed by a bifunctional enzyme (purH).
Acyl-CoA dehydrogenase, C-terminal domain superfamily (Acyl-CoA_dehydrogenase_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal α helical domain superfamily of some bacterial Acyl-CoA dehydrogenases. It is found in association with

,

,

. There is a conserved ARRL sequence motif.
EF2947-like superfamily (EF2947-like_sf)
Type: Homologous_superfamily

This bacterial superfamily of proteins has no known function. The structure of this domain is composed of four helices arranged as a diamond array.
Diphtheria toxin, receptor-binding domain superfamily (Diphtheria_tox_rcpt-bd_dom_sf)
Type: Homologous_superfamily

This entry represents the C-terminal receptor-binding domain (also known as the R domain) of Diphtheria toxin. This domain has a β-sandwich fold consisting of nine strands in two sheet with greek-key topology; it is a subclass of immunoglobin-like fold . The R domain binds to cell surface receptor, permitting the toxin to enter the cell by receptor mediated endocytosis .

Diphtheria toxin (

) is a 58kDa protein secreted by lysogenic strains of Corynebacterium diphtheriae. The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis . The mechanism of inhibition involves transfer of the ADP-ribose group of NAD to elongation factor-2 (EF-2), rendering EF-2 inactive. The catalysed reaction is as follows:

NAD
+
+ peptide diphthamide = nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide

The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution . The structure reveals a Y-shaped molecule of 3 domains, a catalytic domain (fragment A), whose fold is of the α+β type; a transmembrane (TM) domain, which consists of 9 α-helices, 2 pairs of which may participate in pH-triggered membrane insertion and translocation; and a receptor-binding domain, which forms a flattened β-barrel with a jelly-roll-like topology . The TM- and receptor binding-domains together constitute fragment B.
Diphtheria toxin, translocation domain superfamily (Diphtheria_tox_transloc_sf)
Type: Homologous_superfamily

Diphtheria toxin (

) is a 58kDa protein secreted by lysogenic strains of Corynebacterium diphtheriae. The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis . The mechanism of inhibition involves transfer of the ADP-ribose group of NAD to elongation factor-2 (EF-2), rendering EF-2 inactive. The catalysed reaction is as follows:

NAD
+
+ peptide diphthamide = nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide

The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution . The structure reveals a Y-shaped molecule of 3 domains, a catalytic domain (fragment A), whose fold is of the α+β type; a transmembrane (TM) domain, which consists of 9 α-helices, 2 pairs of which may participate in pH-triggered membrane insertion and translocation; and a receptor-binding domain, which forms a flattened β-barrel with a jelly-roll-like topology . The TM- and receptor binding-domains together constitute fragment B.

This entry represents the translocation domain (also known as the T domain) found in the middle of the Diphtheria toxin protein. The T domain has a multi-helical globin-like fold with two additional helices at N-termini, but which has no counterpart to the first globin helix. This domain is thought to unfold in the membrane . pH-induced conformational change in the T domain triggers insertion into the endosomal membrane and facilitates the transfer of the catalytic domain into the cytoplasm .
ATP:guanido phosphotransferase, N-terminal domain superfamily (ATP-guanido_PTrfase_N_sf)
Type: Homologous_superfamily

This domain found in N terminus of ATP:guanido phosphotransferases contains an all-α fold consisting of an irregular array of 6 short helices .

ATP:guanido phosphotransferases are a family of structurally and functionally related enzymes that reversibly catalyse the transfer of phosphate between ATP and various phosphogens. The enzymes belonging to this family include:

Glycocyamine kinase (

), which catalyses the transfer of phosphate from ATP to guanidoacetate.

Arginine kinase (

), which catalyses the transfer of phosphate from ATP to arginine.

Taurocyamine kinase (

), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to taurocyamine. One member is Smc74, a cercaria-specific enzyme from Schistosoma mansoni .

Lombricine kinase (

), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to lombricine.

Creatine kinase (

) (CK) , which catalyses the reversible transfer of high energy phosphate from ATP to creatine, generating phosphocreatine and ADP.

Creatine kinase plays an important role in energy metabolism of vertebrates. There are at least four different, but very closely related, forms of CK. Two isozymes, M (muscle) and B (brain), are cytosolic, while the other two are mitochondrial. In sea urchins there is a flagellar isozyme, which consists of the triplication of a CK-domain. A cysteine residue is implicated in the catalytic activity of these enzymes and the region around this active site residue is highly conserved.
Chemotaxis receptor methyltransferase CheR, N-terminal domain superfamily (CheR_N_sf)
Type: Homologous_superfamily

CheR proteins are part of the chemotaxis signaling mechanism in bacteria. Flagellated bacteria swim towards favourable chemicals and away from deleterious ones. Sensing of chemoeffector gradients involves chemotaxis receptors, transmembrane (TM) proteins that detect stimuli through their periplasmic domains and transduce the signals via their cytoplasmic domains . Signalling outputs from these receptors are influenced both by the binding of the chemoeffector ligand to their periplasmic domains and by methylation of specific glutamate residues on their cytoplasmic domains. Methylation is catalysed by CheR, an S-adenosylmethionine-dependent methyltransferase , which reversibly methylates specific glutamate residues within a coiled coil region, to form gamma-glutamyl methyl ester residues .

The structure of the Salmonella typhimurium chemotaxis receptor methyltransferase CheR, bound to S-adenosylhomocysteine, has been determined to a resolution of 2.0 A . The structure reveals CheR to be a two-domain protein, with a smaller N-terminal helical domain linked via a single polypeptide connection to a larger C-terminal α/β domain. The C-terminal domain has the characteristics of a nucleotide-binding fold, with an insertion of a small anti-parallel β-sheet subdomain. The S-adenosylhomocysteine-binding site is formed mainly by the large domain, with contributions from residues within the N-terminal domain and the linker region .
Transcription elongation factor, GreA/GreB, N-terminal domain superfamily (Tscrpt_elong_fac_GreA/B_N_sf)
Type: Homologous_superfamily

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

YozE-like is a family of Firmicute proteins that carries a four-helix motif similar to sterile alpha motif (SAM) domains. The family is suggested to fall into two subfamilies, possibly with differing functions based on the different surface charges on the three structural representatives, YozE, MW0776 and MW1311. This function is not yet known, although it is likely to involve binding to DNA .
PH1570-like superfamily (PH1570-like_sf)
Type: Homologous_superfamily

This domain is found in a family of proteins that include a hypothetical protein from Pyrococcus horikoshii, which has no known function. It contains six α helices and eight β strands and is thought to be monomeric.
PA1123-like superfamily (PA1123-like_sf)
Type: Homologous_superfamily

This domain superfamily contains three α helices and six β strands. It is found in a protein that is produced from gene PA1123 of Pseudomonas. The protein PA1123 appears to be present in the biofilm layer and may be a lipoprotein.
AF1782-like superfamily (AF1782-like_sf)
Type: Homologous_superfamily

This domain is found in a superfamily of proteins, which have no known function. Its structure is composed of three helices arranged in a close bundle fold with left-handed twist going up-and-down and a mirror topology to the spectrin-like fold.
SMc04008-like superfamily (SMc04008-like_sf)
Type: Homologous_superfamily

This domain superfamily was determined from the crystal structure of a protein of unknown function from Rhizobium meliloti (Sinorhizobium meliloti). The domain is found in a family, which consists of several short bacterial proteins of around 100 residues in length. The function of this domain is unknown. Structurally, this domain is multihelical, it is composed of intertwined homodimer where there are four core helices in each subunits.
Ubiquinol-cytochrome C reductase hinge domain superfamily (Ubol_cytC_Rdtase_hinge_dom_sf)
Type: Homologous_superfamily

The ubiquinol-cytochrome C reductase complex (cytochrome bc1 complex) is a respiratory multienzyme complex . The bc1 complex contains 11 subunits; 3 respiratory subunits (cytochrome B, cytochrome C1, Rieske protein), 2 core proteins and 6 low molecular weight proteins. This family represents the 'hinge' protein of the complex which is thought to mediate formation of the cytochrome c1 and cytochrome c complex. Proteins in this entry form an α-helical hairpin.

This entry represents the structural domain superfamily.
NAD(P)-dependent oxidoreductase domain superfamily (NAD(P)_OxRdtase_dom_sf)
Type: Homologous_superfamily

The aldo-keto reductase family includes a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xylose reductase, rho crystallin, and many others . All possess a similar structure, with a β-α-β fold characteristic of nucleotide binding proteins . The fold comprises a parallel β8/α8 barrel, which contains a novel NADP-binding motif. The binding site is located in a large, deep, elliptical pocket in the C-terminal end of the β-sheet, the substrate being bound in an extended conformation. The hydrophobic nature of the pocket favours aromatic and apolar substrates over highly polar ones .

Binding of the NADPH coenzyme causes a massive conformational change, reorienting a loop, effectively locking the coenzyme in place. This binding is more similar to FAD- than to NAD(P)-binding oxidoreductases .

Some proteins of this entry contain a K+ ion channel beta chain regulatory domain; these are reported to have oxidoreductase activity .
Tachylectin 2 superfamily (Tachylectin2_sf)
Type: Homologous_superfamily

This entry represents a five-bladed β-propeller domain of Tachylectin 2. It consists of five four-stranded antiparallel β-sheets are arranged around a water channel. Tachylectin 2 binds specifically to N-acetylglucosamine and N-acetylgalactosamine and is part of the organism's immunity host defense systems . Tachylectin 2 has five binding sites (one on each β-sheet)for substrate carbohydrate recognition; by combining specificity for N-acetylcarbohydrates with a high density of ligand binding sites, tachylectin 2 is able to recognise foreign sugars.
YqcC-like superfamily (YqcC-like_sf)
Type: Homologous_superfamily

This entry represents the structural domain found in the N-terminal of some tRNA pseudouridine synthase C proteins, as well as other uncharacterised proteins.

Structurally, YqcC is has a bromodomain-like fold, which is composed of four helices arranged in bundle with minor mirror variant of up-and-down topology.
14-3-3 domain superfamily (14-3-3_dom_sf)
Type: Homologous_superfamily

The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells . These are structurally similar phospho-binding proteins that regulate multiple signaling pathways . There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.

The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.
Ribonuclease A-like domain superfamily (RNaseA-like_dom_sf)
Type: Homologous_superfamily

Pancreatic ribonucleases (RNaseA) are pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles . Specifically, the enzymes are involved in endonucleolytic cleavage of 3'-phosphomononucleotides and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates. Ribonuclease can unwind the DNA helix by complexing with single-stranded DNA; the complex arises by an extended multi-site cation-anion interaction between lysine and arginine residues of the enzyme and phosphate groups of the nucleotides. Other proteins belonging to the pancreatic RNAse family include: bovine seminal vesicle and brain ribonucleases; kidney non-secretory ribonucleases ; liver-type ribonucleases ; angiogenin, which induces vascularisation of normal and malignant tissues; eosinophil cationic protein , a cytotoxin and helminthotoxin with ribonuclease activity; and frog liver ribonuclease and frog sialic acid-binding lectin. The sequence of pancreatic RNases contains four conserved disulphide bonds and three amino acid residues involved in the catalytic activity.

This entry represents a domain superfamily found in Ribonuclease A. Its structure is an α+β fold with long curved β sheet and three helices.
Transthyretin/hydroxyisourate hydrolase domain superfamily (Transthyretin/HIU_hydrolase_sf)
Type: Homologous_superfamily

This entry includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this entry do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU . HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage . HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.

Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates . It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) . It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream . The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain . Structurally, it consists of a sandwich fold with seven strands arranged in two sheets and a greek-key topology.