SII-SWORD/CoKE huggingface dataset:
Casein kinase II, regulatory subunit, N-terminal (Casein_kin_II_reg-sub_N)
Type: Homologous_superfamily

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

Serine/threonine-protein kinases

Tyrosine-protein kinases

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

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

Casein kinase, a ubiquitous, well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Ser or Thr in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha and 2 beta subunits . However, some species (e.g., mammals) possess 2 related forms of the alpha-subunit (alpha and alpha'), while others (e.g., fungi) possess 2 related beta-subunits (beta and beta') . The alpha-subunit is the catalytic unit and contains regions characteristic of serine/threonine protein kinases. The beta-subunit is believed to be regulatory, possessing an N-terminal auto-phosphorylation site, an internal acidic domain, and a potential metal-binding motif . The beta subunit is a highly conserved protein of about 25kDa that contains, in its central section, a cysteine-rich motif, CX(n)C, that could be involved in binding a metal such as zinc . The mammalian beta-subunit gene promoter shares common features with those of other mammalian protein kinases and is closely related to the promoter of the regulatory subunit of cAMP-dependent protein kinase .

This superfamily represents the N-terminal α-helical domain, which has an orthogonal bundle topology.
DNA mismatch repair protein MutS, N-terminal (DNA_mismatch_repair_MutS_N)
Type: Homologous_superfamily

Mismatch repair contributes to the overall fidelity of DNA replication and is essential for combating the adverse effects of damage to the genome. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutations or small insertion/deletion loops produced during DNA replication . MutS and MutL are involved in preventing recombination between partially homologous DNA sequences. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotides and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base . MutS can also collaborate with methyltransferases in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch . MutS exists as a dimer, where the two monomers have different conformations and form a heterodimer at the structural level . Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. Mismatch binding induces ATP uptake and a conformational change in the MutS protein, resulting in a clamp that translocates on DNA.

This entry represents the N-terminal domain of proteins in the MutS family of DNA mismatch repair proteins. The N-terminal domain of MutS is responsible for mismatch recognition and forms a 6-stranded mixed β-sheet surrounded by three α-helices, which is similar to the structure of tRNA endonuclease.
Phosphotransferase/anion transporter (PTrfase/Anion_transptr)
Type: Homologous_superfamily

This superfamily represents a structural domain found as the cytoplasmic domain in certain anion transporter proteins , and as domain IIa in mannitol-specific and ntr (nitrogen regulatory) phosphotransferases .

This domain adopts a 3-layer α/β/α structure in the order, β-α(2)-β(3)-α(3). This domain can be elaborated with additional secondary structure in anion transporter proteins.
Heat shock protein Hsp33, N-terminal (Heat_shock_Hsp33_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal, 3-layer β/α/β domain from the heat shock protein Hsp33. Hsp33 is a molecular chaperone, distinguished from all other known chaperones by its mode of functional regulation. Its activity is redox regulated. Hsp33 is a cytoplasmically localised protein with highly reactive cysteines that respond quickly to changes in the redox environment. Oxidizing conditions like H
2
O
2
cause disulphide bonds to form in Hsp33, a process that leads to the activation of its chaperone function .
Heat shock protein Hsp33, C-terminal (Heat_shock_Hsp33_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal α/β domain from the heat shock protein Hsp33. Hsp33 is a molecular chaperone, distinguished from all other known chaperones by its mode of functional regulation. Its activity is redox regulated. Hsp33 is a cytoplasmically localised protein with highly reactive cysteines that respond quickly to changes in the redox environment. Oxidizing conditions like H
2
O
2
cause disulphide bonds to form in Hsp33, a process that leads to the activation of its chaperone function .
Molybdopterin synthase/thiamin biosynthesis sulphur carrier, beta-grasp (Mopterin_synth/thiamin_S_b)
Type: Homologous_superfamily

This entry represents a structural domain with a β-grasp fold that is found in molybdopterinsynthase subunit MoaD , as well as in the thiamin biosynthesis sulphur carrier protein ThiS .

ThiS (thiaminS) is a 66 aa protein involved in sulphur transfer. ThiS is coded in the thiCEFSGH operon in Escherichia coli. ThiS proteins have two conserved Glycines at the COOH terminus. Thiocarboxylate is formed at the last G in the activation process. Sulphur is transferred from ThiI to ThiS in a reaction catalysed by IscS . MoaD, a protein involved in sulphur transfer during molybdopterin synthesis, is about the same length and shows limited sequence similarity to ThiS. Both have the conserved GG at the COOH end.
FAD/NAD-linked reductase, dimerisation domain superfamily (FAD/NAD-linked_Rdtase_dimer_sf)
Type: Homologous_superfamily

This superfamily represents a dimerisation domain that is usually found at the C-terminal of FAD and NAD-linked reductases. This domain has a core α+β sandwich structure consisting of beta(3,4)-alpha(3). The first two domains are of the same β/β/α fold. This domain can be found in the following proteins:

Glutathione reductase .

Trypanothione reductase .

Mammalian thioredoxin reductase .

Apoptosis-inducing factor (AIF), which contains a large loop insertion in this domain .

NADH peroxidase .

Biphenyl 2,3-dioxygenase, ferredoxin reductase (also known as NADH-dependent ferredoxin reductase, BphA4) .

Putidaredoxin reductase .

Dihydrolipoyl dehydrogenase (also known as dihydrolipoamide dehydrogenase) .

2-oxopropyl-CoM reductase, carboxylating (also known as NADH-dependent 2-ketopropyl coenzyme M oxidoreductase/carboxylase) .

The flavin-binding subunit of flavocytochrome c sulphide dehydrogenase (FCSD) .

NADH oxidase /nitrite reductase.
Cullin, conserved site (Cullin_CS)
Type: Conserved_site

Cullins are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases (E3). Cullins are found throughout eukaryotes. Humans express several cullins (Cul1, 2, 3, 4A, 4B, 5, 7 and 9), each forming part of a multi-subunit ubiquitin complex . Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) , play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins .

This entry represents a conserved site found in various cullin proteins.
Cullin homology domain (Cullin_homology)
Type: Domain

Cullins are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases (E3). Cullins are found throughout eukaryotes. Humans express several cullins (Cul1, 2, 3, 4A, 4B, 5, 7 and 9), each forming part of a multi-subunit ubiquitin complex . Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) , play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins .
Cullin repeat-like-containing domain superfamily (Cullin_repeat-like_dom_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal cullin repeat-containing domain; these repeats form a domain with a multi-helical 2-layered α/α structure, which in turn is folded into a right-handed superhelix. A similar structural domain is found in exocyst complex components such as EXO70 and EXO84.

Cullins are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases (E3). Cullins are found throughout eukaryotes. Humans express several cullins (Cul1, 2, 3, 4A, 4B, 5, 7 and 9), each forming part of a multi-subunit ubiquitin complex . Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) , play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins .
Aldehyde dehydrogenase, cysteine active site (Ald_DH_CS_CYS)
Type: Conserved_site

Aldehyde dehydrogenases (

and

) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known : class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase. These residues are conserved in all the enzymes of this entry. This entry represents the cysteine active site.

This entry also includes Retinal dehydrogenase 2 that share similar active site. This enzyme catalyses the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively . It lacks activity with benzaldehyde, acetaldehyde and octanal .
Aldehyde/histidinol dehydrogenase (Ald_DH/histidinol_DH)
Type: Homologous_superfamily

This entry represents a structural domain found in aldehyde dehydrogenases and histidinol dehydrogenases . These proteins contain two similar domains, each with a 3-layer α/β/α structure, which probably arose from a duplication. These enzymes bind NAD differently from other NAD(P)-dependent oxidoreductases.

Aldehyde dehydrogenases (

and

) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known : class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase.

Histidinol dehydrogenase (

) (HDH) catalyses the terminal step in the biosynthesis of histidine in bacteria, fungi, and plants, the four-electron oxidation of L-histidinol to histidine. In 4-electron dehydrogenases, a single active site catalyses 2 separate oxidation steps: oxidation of the substrate alcohol to an intermediate aldehyde; and oxidation of the aldehyde to the product acid, in this case His . The reaction proceeds via a tightly- or covalently-bound inter-mediate, and requires the presence of 2 NAD molecules . By contrast with most dehydrogenases, the substrate is bound before the NAD coenzyme . A Cys residue has been implicated in the catalytic mechanism of the second oxidative step . In bacteria HDH is a single chain polypeptide; in fungi it is the C-terminal domain of a multifunctional enzyme which catalyzes three different steps of histidine biosynthesis; and in plants it is expressed as nuclear encoded protein precursor which is exported to the chloroplast .

This entry also includes Retinal dehydrogenase 2 that share similar active site. This enzyme catalyses the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively . It lacks activity with benzaldehyde, acetaldehyde and octanal .
Aldehyde dehydrogenase, N-terminal (Ald_DH_N)
Type: Homologous_superfamily

This superfamily represents a structural domain found at the N-terminal of aldehyde dehydrogenases . These proteins contain two similar domains, each with a 3-layer α/β/α structure, which probably arose from a duplication; this entry covers the N-terminal a/b/a domain. These enzymes binds NAD differently from other NAD(P)-dependent oxidoreductases.
Aldehyde dehydrogenase, C-terminal (Ald_DH_C)
Type: Homologous_superfamily

This superfamily represents a structural domain found at the C-terminal of aldehyde dehydrogenases . These proteins contain two similar domains, each with a 3-layer α/β/α structure, which probably arose from a duplication; this entry covers the C-terminal a/b/a domain. These enzymes bind NAD differently from other NAD(P)-dependent oxidoreductases.
FAD-linked oxidase-like, C-terminal (FAD-linked_Oxase-like_C)
Type: Homologous_superfamily

This superfamily represents a structural domain found at the C-terminal of several FAD-linked oxidases. This domain consists of two structural subdomains: subdomain 1 is a 2-layer a/b or 3-layer a/b/a sandwich, and subdomain 2 is either an orthogonal α-bundle or a second 2-layer a/b sandwich. It can be found in the following proteins:

Vanillyl-alcohol family, which includes the flavoprotein vanillyl-alcohol oxidase (

) as well as the flavoprotein subunit of p-cresol methylhydroxylase (

) (the other subunit being a short chain cytochrome c) , both of these enzymes contain covalently bound FAD.

D-lactate dehydrogenases (

,

-cytochrome), a peripheral membrane respiratory enzyme involved in electron transfer for the energization of active transport of a variety of sugars and amino acids in bacteria .

Cholesterol oxidases (

), a monomeric flavoenzyme that catalyses the oxidation and isomerisation of cholesterol to cholest-4-en-3-one .

Cytokinin dehydrogenase 1 (

), which has a major role in the control of plant cytokinin hormone levels by catalysing their irreversible oxidation .
FAD-binding domain, PCMH-type (FAD-bd_PCMH)
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) theferredoxin reductase (FR)-type FAD-binding domain,(ii) the FAD-binding domains that adopt a Rossmann fold and (iii) the p-cresol methylhydroxylase (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 PCMH-type FAD-binding domain consists of two α-β subdomains: one is composed of three parallel β-strands (B1-B3) surrounded by α-helices, and is packed against the second subdomain containing five antiparallel β-strands (B4-B8) surrounded by α-helices . The two subdomains accommodate the FAD cofactor between them . In the PCMH proteins the coenzyme FAD is also covalently attached to a tyrosine located outside the FAD-binding domain in the C-terminal catalytic domain .

This domain is found in various enzymes including:

FAD-linked oxidases (N-terminal domain), such as vanillyl-alochol oxidase (

) , flavoprotein subunit of p-cresol methylhydroxylase (

) , D-lactate dehydrogenases (

,

-cytochrome) , cholesterol oxidases (

) , and cytokinin dehydrogenase 1 (

) .

Uridine diphospho-N-acetylenolpyruvylglucosamine reductase (MurB) (N-terminal domain) .

CO dehydrogenase flavoprotein (N-terminal domain; ) family, which includes xanthine oxidase (domain 3) (

) , subunit A of xanthine dehydrogenase (domain 3) (

) , medium subunit of quinoline 2-oxidoreductase (QorM) (

) , and the beta-subunit of 4-hydroxybenzoyl-CoA reductase (HrcB) (N-terminal domain) (

) .
FAD-binding, type PCMH, subdomain 1 (FAD-bd_PCMH_sub1)
Type: Homologous_superfamily

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 p-cresol methylhydroxylase (PCMH)-type FAD-binding domain .

The PCMH-type FAD-binding domain consists of two α-β subdomains: one is composed of three parallel β-strands (B1-B3) surrounded by α-helices, and is packed against the second subdomain containing five antiparallel β-strands (B4-B8) surrounded by α-helices . The two subdomains accommodate the FAD cofactor between them . This superfamily represents the first (N-terminal) subdomain, which is found in:

FAD-linked oxidases (N-terminal domain), such as vanillyl-alochol oxidase (

) , flavoprotein subunit of p-cresol methylhydroxylase (

) , D-lactate dehydrogenases (

,

-cytochrome) , Cholesterol oxidases (

) , Cytokinin dehydrogenase 1 (

) .

Uridine diphospho-N-acetylenolpyruvylglucosamine reductase (MurB) (N-terminal domain) .

CO dehydrogenase flavoprotein (N-terminal domain; ) family.
FAD-binding, type PCMH, subdomain 2 (FAD-bd_PCMH_sub2)
Type: Homologous_superfamily

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 p-cresol methylhydroxylase (PCMH)-type FAD-binding domain .

The PCMH-type FAD-binding domain consists of two α-β subdomains: one is composed of three parallel β-strands (B1-B3) surrounded by α-helices, and is packed against the second subdomain containing five antiparallel β-strands (B4-B8) surrounded by α-helices . The two subdomains accommodate the FAD cofactor between them . This superfamily represents the second (C-terminal) subdomain, which is found in:

CO dehydrogenase flavoprotein (N-terminal domain; ) family, which includes xanthine oxidase (domain 3) (

) , subunit A of xanthine dehydrogenase (domain 3) (

) , and the beta-subunit of 4-hydroxybenzoyl-CoA reductase (HrcB) (N-terminal domain) (

) .

Uridine diphospho-N-acetylenolpyruvylglucosamine reductase (MurB) (N-terminal domain) .

Magnesium and cobalt efflux protein CorC .

D-arabinono-1,4-lactone oxidase .

K(+)/H(+) antiporter NhaP2.
Cytokinin dehydrogenase, C-terminal domain superfamily (Cytok_DH_C_sf)
Type: Homologous_superfamily

This domain superfamily is found towards the C terminus of cytokinin dehydrogenase and vanillyl-alcohol oxidase.
Vanillyl-alcohol oxidase, C-terminal subdomain 2 (Vanillyl_alc_oxidase_C-sub2)
Type: Homologous_superfamily

The C-terminal domain of certain FAD-linked oxidases consist of two structural subdomains: subdomain 1 is a 2-layer a/b or 3-layer a/b/a sandwich, and subdomain 2 is either an orthogonal α-bundle or a second 2-layer a/b sandwich. This superfamily represents the second (C-terminal) subdomain with an orthogonal α-bundle fold. This subdomain is found in members of the vanillyl-alcohol family, which includes the flavoprotein vanillyl-alcohol oxidase (

) as well as the flavoprotein subunit of p-cresol methylhydroxylase (

) (the other subunit being a short chain cytochrome c) , both of these enzymes contain covalently bound FAD.