SII-SWORD/CoKE huggingface dataset:
Cyclotide, bracelet, conserved site (Cyclotide_bracelet_CS)
Type: Conserved_site

Cyclotides (cyclo peptides) are plant peptides of ~30 amino acids with a head to-tail cyclic backbone and six cysteine residues involved in three disulphide bonds. The cyclotides are extremely resistant to proteolysis and are remarkably stable. Cyclotides display a diverse range of biological activities, including uterotonic activity, inhibition of neurotensin binding, hemolytic, anti-HIV and anti-microbial activity. This range of biological activities makes cyclotides amenable to potential pharmaceutical and agricultural applications. Although their precise role in plants has not yet been reported, it appears that they are most likely present as defence molecules .

The three-dimensional structure of cyclotides is compact and contains a number of β-turns, three β-strands arranged in a distorted triple-stranded β-sheet, a short helical segment, and a network of disulphide bonds which form a cystine knot. The cystine knot consists of an embedded ring in the structure, formed by two disulphide bonds and their connecting backbone segments is threaded by a third disulphide bond. Although the cystine knot motif is now well known in a wide variety of proteins, the cyclotides remain as the only example in which a cystine knot is embedded within a circular protein backbone, a motif that is referred to as the cyclic cystine knot (CCK) .

Cyclotides can be separated into two sub-families, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularisation of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip . Bracelet and Moebius families of cyclotides possess a Knottin scaffold. The cyclotide family of proteins is abundant in plants from the Rubiaceae and Violaceae families and includes:

Kalata B1.

Circulins.

Cyclopsychotride A.

Cycloviolacin O1.

Also included in this entry are cliotides from the leguminous plant Clitoria ternatea. These are cyclotides with known medicinal properties that have antimicrobial activities against Escherichia coli and are cytotoxic to HeLa cells .

This entry is found in the bracelet subfamily and represents a conserved site containing the first three cysteines.
Cyclotide, moebius, conserved site (Cyclotide_moebius_CS)
Type: Conserved_site

Cyclotides (cyclo peptides) are plant peptides of ~30 amino acids with a head to-tail cyclic backbone and six cysteine residues involved in three disulphide bonds. The cyclotides are extremely resistant to proteolysis and are remarkably stable. Cyclotides display a diverse range of biological activities, including uterotonic activity, inhibition of neurotensin binding, hemolytic, anti-HIV and anti-microbial activity. This range of biological activities makes cyclotides amenable to potential pharmaceutical and agricultural applications. Although their precise role in plants has not yet been reported, it appears that they are most likely present as defence molecules .

The three-dimensional structure of cyclotides is compact and contains a number of β-turns, three β-strands arranged in a distorted triple-stranded β-sheet, a short helical segment, and a network of disulphide bonds which form a cystine knot. The cystine knot consists of an embedded ring in the structure, formed by two disulphide bonds and their connecting backbone segments is threaded by a third disulphide bond. Although the cystine knot motif is now well known in a wide variety of proteins, the cyclotides remain as the only example in which a cystine knot is embedded within a circular protein backbone, a motif that is referred to as the cyclic cystine knot (CCK) .

Cyclotides can be separated into two sub-families, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularisation of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip . Bracelet and Moebius families of cyclotides possess a Knottin scaffold. The cyclotide family of proteins is abundant in plants from the Rubiaceae and Violaceae families and includes:

Kalata B1.

Circulins.

Cyclopsychotride A.

Cycloviolacin O1.

Also included in this entry are cliotides from the leguminous plant Clitoria ternatea. These are cyclotides with known medicinal properties that have antimicrobial activities against Escherichia coli and are cytotoxic to HeLa cells .

This entry is found in the moebius subfamily and represents a conserved site containing the first three cysteines.
Assassin bug toxin-like (Assassin_bug_toxin-like)
Type: Family

Assassin bugs (Arthropoda:Insecta:Hemiptera:Reduviidae), sometimes known as conenose or kissing bugs, are one of the largest and morphologically diverse families of true bugs feeding on crickets, caterpillars and other insects. Some assassin bug species are bloodsucking parasites of mammals, even of human. They can be commonly found throughout most of the world and their size varies from a few millimetres to as much as 3 or 4 centimetres. The toxic saliva of the predatory assassin bugs contains a complex mixture of small and large peptides for diverse uses such as immobilising and pre-digesting their prey, and defence against competitors and predators. Assassin bug toxins are small peptides with disulfide connectivity that target ion-channels. They are relatively homologous to the calcium channel blockers omega-conotoxins from marine cone snails and belong to the four-loop cysteine scaffold structural class , .

One of these small proteins, Ptu1, blocks reversibly the N-type calcium channels, but at the same time is less specific for the L-or P/Q-type calcium channels . Ptu1 is 34 amino acid residues long and is cross-linked by three disulphide bridges. Ptu1 contains a β-sheet region made of two antiparallel β-strands and consists of a compact disulphide-bonded core from which four loops emerge as well as N-and C-termini . Some assassin bug toxins are listed below:

Agriosphodrus dohrni (Assassin bug) toxin Ado1.

Isyndus obscurus (Assassin bug) toxin Iob1.

Peirates turpis (Assassin bug) toxin Ptu1.

This entry also includes U-limacoditoxin(3)-Dv21 from mottled cup moth , a probable toxin with moderate antiparasitic activity against the nematode Haemonchus contortus.
D12 class N6 adenine-specific DNA methyltransferase (MeTrfase_D12)
Type: Family

In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. There are 2 major classes of DNA methyltransferase that differ in the nature of the modifications they effect. The members of one class (C-MTases) methylate a ring carbon and form C5-methylcytosine (see

). Members of the second class (N-MTases) methylate exocyclic nitrogens and form either N4-methylcytosine (N4-MTases) or N6-methyladenine (N6-MTases). Both classes of MTase utilise the cofactor S-adenosyl-L-methionine (SAM) as the methyl donor and are active as monomeric enzymes .

N-6 adenine-specific DNA methylases (

) (A-Mtase) are enzymes that specifically methylate the amino group at the C-6 position of adenines in DNA. Such enzymes are found in the three existing types of bacterial restriction-modification systems (in type I system the A-Mtase is the product of the hsdM gene, and in type III it is the product of the mod gene). All of these enzymes recognise a specific sequence in DNA and methylate an adenine in that sequence. It has been shown that A-Mtases contain a conserved motif Asp/Asn-Pro-Pro-Tyr/Phe in their N-terminal section, this conserved region could be involved in substrate binding or in the catalytic activity. The structure of N6-MTase TaqI (M.TaqI) has been resolved to 2.4 A . The molecule folds into 2 domains, an N-terminal catalytic domain, which contains the catalytic and cofactor binding sites, and comprises a central 9-stranded β-sheet, surrounded by 5 helices; and a C-terminal DNA recognition domain, which is formed by 4 small β-sheets and 8 α-helices. The N- and C-terminal domains form a cleft that accommodates the DNA substrate. A classification of N-MTases has been proposed, based on conserved motif (CM) arrangements . According to this classification, N6-MTases that have a DPPY motif (CM II) occuring after the FxGxG motif (CM I) are designated D12 class N6-adenine MTases.
Chalcone/stilbene synthase, C-terminal (Chalcone/stilbene_synt_C)
Type: Domain

Chalcone synthases (CHS) (

) and stilbene synthases (STS) (formerly known as resveratrol synthases) are related plant enzymes. CHS is an important enzyme in flavanoid biosynthesis and STS is a key enzyme in stilbene-type phyloalexin biosynthesis. Both enzymes catalyse the addition of three molecules of malonyl-CoA to a starter CoA ester (a typical example is 4-coumaroyl-CoA), producing either a chalcone (with CHS) or stilbene (with STS) . These enzymes have a conserved cysteine residue, located in the central section of the protein sequence, which is essential for the catalytic activity of both enzymes and probably represents the binding site for the 4-coumaryl-CoA group .

This domain of chalcone synthase is reported to be structurally similar to domains in thiolase and beta-ketoacyl synthase. The differences in activity are accounted for by differences in the N-terminal domain .
Clathrin, heavy chain, linker (Clathrin_H-chain_linker)
Type: Homologous_superfamily

Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport . Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors .

Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion . The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase . Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process . The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins .

This entry represents the α-helical zigzag linker region connecting the conserved N-terminal β-propeller region to the C-terminal α-α-superhelical region in clathrin heavy chains .
Autotransporter, pectate lyase C-like domain superfamily (Autotransporter_pectin_lyase_C)
Type: Homologous_superfamily

Secretion of protein products occurs by a number of different pathways in bacteria. One of these pathways known as the type V pathway was first described for the IgA1 protease . The protein component that mediates secretion through the outer membrane is contained within the secreted protein itself, hence the proteins secreted in this way are called autotransporters .

This superfamily represents the pectate Lyase C-like domain found in autotransporters. This domain can also be found in phage P22 tail spike protein.
Pectin lyase fold (Pectin_lyas_fold)
Type: Homologous_superfamily

This entry covers proteins that are closely related to the pectolytic enzyme, pectin lyase, which act as virulence factors. These proteins include pectate lyase, iota-carrageenase, and glycoside hydrolases from family 28 (such as galacturonases). Pectin lyases, pectate lyases and galacturonases all act on forms of pectin, one of the main components of the cell wall. When the backbone of pectin is methylated it is known as pectin, and can be cleaved by pectin lyase, a microbial virulence factor . When the backbone of pectin is demethylated it is known as pectate, and can be cleaved by pectate lyase virulence factors, or hydrolysed by polygalacturonases . Iota-carrageenase is an enzyme that degrades carrageenan, a main component of the cell walls of various marine red algae. Unlike other carrageenase enzymes, iota-carrageenase belongs to the glycoside hydrolase structural family . All these enzymes display a β-helical structure.
Thioredoxin-like fold (Thioredoxin-like_fold)
Type: Domain

Several biological processes regulate the activity of target proteins through changes in the redox state of thiol groups (S2 to SH2), where a hydrogen donor is linked to an intermediary disulphide protein. Such processes include the ferredoxin/thioredoxin system, the NADP/thioredoxin system, and the glutathione/glutaredoxin system . Several of these disulphide proteins share a common structure, consisting of a three-layer α/β/α core.
Ribonuclease H-like superfamily (RNaseH-like_sf)
Type: Homologous_superfamily

The catalytic domain of several polynucleotidyl transferases share a similar structure, consisting of a 3-layer α/β/α fold that contains mixed β-sheets, suggesting that they share a similar mechanism of catalysis. Polynucleotidyl transferases containing this domain include ribonuclease H class I (RNase HI) and class II (RNase HII), HIV RNase (reverse transcriptase domain), retroviral integrase (catalytic domain), Mu transposase (core domain), transposase inhibitor Tn5 (containing additional all-α subdomains), DnaQ-like 3'-5' exonucleases (exonuclease domains), RuvC resolvase, and mitochondrial resolvase ydc2 (catalytic domain) .

This superfamily also includes the YqgF domain, described as RNase H-like and typified by the Escherichia coli protein YqgF . YqgF domain-containing proteins are predicted to be ribonucleases or resolvases based on homology to RuvC Holliday junction resolvases.
Beta-lactamase/transpeptidase-like (Beta-lactam/transpept-like)
Type: Homologous_superfamily

This superfamily represents a beta-lactamase structural motif, which contains a cluster of α-helices and an α/β sandwich. In addition to beta-lactamases, this domain is also found in D-ala carboxypeptidase/transpeptidase, esterase (EstB) , the penicillin receptor BlaR (C-terminal domain), D-aminopeptidase (N-terminal domain) , penicillin-biding proteins (e.g. PBP2x, PBP5), and in glutaminase (GlnA). Beta-lactamases are the most common bacterial resistance mechanism against beta-lactam antibiotics . Beta-lactamases appear to have evolved from DD-transpeptidases, which are penicillin-binding proteins involved in cell wall biosynthesis, and as such are one of the main targets of beta-lactam antibiotics.
Bacteriophage T4, Gp32, single-stranded DNA-binding domain (Phage_T4_Gp32_ssDNA-bd)
Type: Domain

This entry represents the Bacteriophage T4, Gp32, single-stranded DNA-binding domain. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.

Single-stranded DNA-binding protein (also known as Gp32 or SSB) is essential for bacteriophage T4 DNA replication, recombination and repair, acting to stimulate replisome processing and accuracy through its binding to ssDNA as the replication fork advances . The crystal structure of Gp32 shows an ssDNA binding cleft comprised of regions from three structural subdomains, through which ssDNA can slide freely . The structure of Gp32 is similar to other phage ssDNA-binding proteins such as Gp2.5 from bacteriophage T4, and gene V protein, both of which have a nucleic acid-binding OB-type fold. However, Gp32 contains a zinc-finger subdomain at residues 63-111 that is not found in the other two phage proteins.

This protein stimulates the activities of viral DNA polymerase and DnaB-like SF4 replicative helicase, probably via its interaction with the helicase assembly factor , and together with DnaB-like SF4 replicative helicase and the helicase assembly factor, promotes pairing of two homologous DNA molecules containing complementary single-stranded regions and mediates homologous DNA strand exchange .
Nucleic acid-binding, OB-fold (NA-bd_OB-fold)
Type: Homologous_superfamily

A five-stranded β-barrel was first noted as a common structure among four proteins binding single-stranded nucleic acids (staphylococcal nuclease and aspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold, a five-stranded β-sheet coiled to form a closed β-barrel capped by an α helix located between the third and fourth strands . Two ribosomal proteins, S17 and S1, are members of this class and have different variations of the OB fold theme. Comparisons with other OB fold nucleic acid binding proteins suggest somewhat different mechanisms of nucleic acid recognition in each case .

There are many nucleic acid-binding proteins that contain domains with this OB-fold structure, including:

Large ribosomal subunit protein uL2

Small ribosomal subunit protein uS12

DNA ligase

Polyribonucleotide nucleotidyltransferase

Phage ssDNA-binding proteins (gp32, gp2.5, gpV)

Holliday junction branch migration complex subunit RuvA

Elongation factor P
Six-hairpin glycosidase-like superfamily (6hp_glycosidase-like_sf)
Type: Homologous_superfamily

This domain superfamily contains up to seven α-hairpins arranged in closed circular array.

The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([ec:2.4.1.-]) and related proteins into distinct sequence based families has been described . This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.
Matrix protein, lentiviral and alpha-retroviral, N-terminal (Matrix_HIV/RSV_N)
Type: Homologous_superfamily

Retroviral matrix proteins (or major core proteins) are components of envelope-associated capsids, which line the inner surface of virus envelopes and are associated with viral membranes . Matrix proteins are produced as part of Gag precursor polyproteins. During viral maturation, the Gag polyprotein is cleaved into major structural proteins by the viral protease, yielding the matrix (MA), capsid (CA), nucleocapsid (NC), and some smaller peptides. Gag-derived proteins govern the entire assembly and release of the virus particles, with matrix proteins playing key roles in Gag stability, capsid assembly, transport and budding. Although matrix proteins from different retroviruses appear to perform similar functions and can have similar structural folds which predominantly consist of four closely packed α-helices that are interconnected through loops, their primary sequences can be very different .

This entry represents the N-terminal domain from matrix proteins from primate lentiviruses, such as human and simian immunodeficiency viruses (HIV and SIV, respectively), equine lentiviruses, such as Equine infectious anemia virus (EIAV), and avian alpha-retroviruses such as Rous sarcoma virus (RSV), and type C retroviruses, such as Avian sarcoma virus, respectively . This entry also identifies matrix proteins from several eukaryotic endogenous retroviruses, which arise when one or more copies of the retroviral genome becomes integrated into the host genome .
p53/RUNT-type transcription factor, DNA-binding domain superfamily (p53/RUNT-type_TF_DNA-bd_sf)
Type: Homologous_superfamily

This DNA-binding domain superfamily is found in the p53 and the RUNT families of transcription factors. The DNA-binding domain acts to clamp or encircle the DNA target in order to stabilise the protein-DNA complex. This domain has an immunoglobulin-like fold consisting of a β-sandwich of 9 strands in two sheets with a Greek key topology .
Ferritin-like (Ferritin-like)
Type: Homologous_superfamily

This entry represents ferritin and structurally related proteins. Ferritin is a major non-haem iron storage protein in animal, plants and microorganisms . Iron is required by most organisms, but is potentially toxic due to its reactivity, which is counteracted by sequestering it into ferritin. Ferritin consists of a 4-helical bundle core, and contains a bimetal-ion centre in the middle of the bundle. Other proteins with this structure include: haem-containing bacteriferritins; rubrerythrin, which appears to have a role in anaerobic detoxification pathway for reactive oxygen species ; Dps (DNA-binding proteins from starved cells) used in bacteria for iron storage-detoxification; and CRD1 (AcsF), which is required for the maintenance of photosystem I .
Ribonucleotide reductase-like (RNR-like)
Type: Homologous_superfamily

The R2 protein of ribonucleotide reductase catalyses the reduction of all four ribonucleotides to deoxyribonucleotides for use in DNA synthesis. This catalysis involves generating and storing a tyrosyl radical, which is essential for ribonucleotide reduction. The crystal structure consists of a core of four helices in a closed bundle with a left-handed twist and one crossover connection, and a bimetal-ion centre in the middle of the bundle .

This entry represents proteins that are structurally related to the R2 protein of class I ribonucleotide reductase, including the alpha and beta subunits of methane monooxygenase, and delta 9-stearoyl-acyl carrier protein desaturase .
FMN-binding split barrel (Split_barrel_FMN-bd)
Type: Homologous_superfamily

The FMN-binding domain has a split β-barrel structure with a Greek-key topology that is related in structure to the ferredoxin reductase-like FAD-binding domain. The FMN-binding split barrel domain is found in pyridoxine 5'-phoshate oxidase (PNP oxidase), FMN-binding protein, ferric reductase, and in phenol 2-hydroxylase component B (PheA2).

PNP oxidase (

) is an FMN flavoprotein that catalyses the oxidation of pyridoxamine-5-P (PMP) and pyridoxine-5-P (PNP) to pyridoxal-5-P (PLP). This reaction serves as the terminal step in the de novo biosynthesis of PLP in Escherichia coli, and as a part of the salvage pathway of this coenzyme in both E. coli and mammalian cells . The binding sites for FMN and for substrate have been highly conserved throughout evolution.

The FMN-binding protein (FMN-bp) is one of the smallest proteins known to bind FMN. FMN-bp appears to participate in the electron-transfer pathway, and may have a structural relationship to the C-terminal domain of chymotrypsin .

Microbial ferric reductases are essential for generating more soluble ferrous iron to use in cellular proteins (assimilatory ferric reductases), and as terminal reductases of iron respiratory pathway of certain bacteria (dissimilatory iron reductases). Most assimilatory iron reductases are flavin enzymes .