SII-SWORD/CoKE huggingface dataset:
NSP1, globular domain, alpha/betacoronavirus (a/bCoV_NSP1_glob)
Type: Domain

This is the globular domain of NSP1 from alpha and betacoronavirus.

Nonstructural protein 1 (NSP1) is a critical virulence factor of coronaviruses (CoV) and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. NSP1 is a characteristic feature of alpha and betacoronavirus, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses . NSP1 binds to the 40S ribosomal subunit and inhibits host translation, and it also induces a template-dependent endonucleolytic cleavage of host mRNAs , while viral mRNAs are less susceptible to NSP1-mediated inhibition of translation, because of their 5'-end leader sequence . NSP1 also suppresses the host innate immune functions by inhibiting type I interferon expression and host antiviral signalling pathways. The C-terminal domain binds to the mRNA entry tunnel interfering with mRNA binding (

) . NSP1 consists of a globular domain arranged in a mixed parallel/antiparallel 6-stranded β-barrel with an α-helix covering one end of the barrel and another helix alongside the barrel . In addition to the globular domain, bCoV NSP1s have a C-terminal domain .
SARS-like ORF8 accessory protein, Ig-like domain (SARS_ORF8_IG)
Type: Domain

Coronaviruses (CoVs) have a similar genomic structure and encodes four structural proteins (S, E, M and N) and a variable number of accessory proteins. Accessory proteins play an important role in virus-host interactions, especially in antagonising or regulating host immunity and virus adaptation to the host. There are large variations in the number of accessory proteins (1-10) among coronaviruses. BetaCoVs have 3-5 accessory proteins, except for SARS-CoV and SARS-CoV-2, which possess the largest number of accessory proteins among all coronaviruses (10 and 9, respectively). ORF8 is the most variable accessory protein among those encoded by SARS related coronaviruses (SARSr-CoVs) and is
not shared by all members of subgenus Sarbecovirus. SARSr ORF8 accessory proteins are characterised by the presence of an N-terminal hydrophobic signal peptide, a conserved N-glycosylation site, and enough cysteine residues with the potential to form disulfide bonds, drawing their picture as structurally stable potential ER-resident proteins. There is functional overlap between these proteins with involvement in immune modulation, which is probably accomplished through involvement in protein quality control. When ORF8 is exogenously overexpressed in cells, it disrupts IFN-I signalling. Unlike ORF8a/b of SARS-CoV, the SARS-CoV-2 ORF8 downregulates MHC-I in cells.

This entry represents the immunoglobulin (Ig)-like domain from SARSr ORF8 .
3a-like viroporin, transmembrane domain, alpha/betacoronavirus (a/bCoV_VIROPORIN_3A-like_TM)
Type: Domain

All coronaviruses have a similar genomic structure comprising two large open reading frames (ORFs) (ORF1a and ORF1b) encoding the coronavirus replicase. At the 3' end, the genome encodes four structural proteins (S, E, M and N) and a variable number of accessory proteins. Accessory proteins play an important role in virus-host interactions, especially in antagonizing or regulating host immunity and virus adaptation to the host. There are large variations in the number of accessory proteins (1-10) among coronaviruses. Betacoronavirus (bCoVs) have 3-5 accessory proteins, except for SARS-CoV and SARS-CoV-2, which possess the largest number of accessory proteins among all coronaviruses (10 and 9, respectively). 3a-like accessory proteins are found in multiple alpha and betacoronavirus lineages that infect bats and humans. They are transmembrane proteins of the viroporin family that form ion channels in the host membrane and have been implicated in inducing apoptosis, pathogenicity, and virus release. The induction of cytokine storms in COVID-19 patients might be linked to ORF3a mediated activation of inflammasome. 3a-like viroporins contain a transmembrane domain (TM) and a cytosolic domain (CD) .

This is the transmembrane domain (TM) of 3a-like viroporins, which is composed of three helices. The 3a-like viroporin forms a dimer and the six transmembrane helices of the dimer form an ion channel with polar/charged residues in the interior of the channel capable of conducting cations .
3a-like viroporin, cytosolic domain, alpha/betacoronavirus (a/bCoV_VIROPORIN_3A-like_CD)
Type: Domain

All coronaviruses have a similar genomic structure comprising two large open reading frames (ORFs) (ORF1a and ORF1b) encoding the coronavirus replicase. At the 3' end, the genome encodes four structural proteins (S, E, M and N) and a variable number of accessory proteins. Accessory proteins play an important role in virus-host interactions, especially in antagonizing or regulating host immunity and virus adaptation to the host. There are large variations in the number of accessory proteins (1-10) among coronaviruses. Betacoronavirus (bCoVs) have 3-5 accessory proteins, except for SARS-CoV and SARS-CoV-2, which possess the largest number of accessory proteins among all coronaviruses (10 and 9, respectively). 3a-like accessory proteins are found in multiple alpha and betacoronavirus lineages that infect bats and humans. They are transmembrane proteins of the viroporin family that form ion channels in the host membrane and have been implicated in inducing apoptosis, pathogenicity, and virus release. The induction of cytokine storms in COVID-19 patients might be linked to ORF3a mediated activation of inflammasome. 3a-like viroporins contain a transmembrane domain (TM) and a cytosolic domain (CD) .

This is the cytosolic domain (CD) of 3a-like viroporins, which consists of two antiparallel β-sheets forming a β-sandwich. The 3a-like viroporin forms a dimer and the six transmembrane helices of the dimer form an ion channel with polar/charged residues in the interior of the channel capable of conducting cations .
DENR, C-terminal domain (DENR_C)
Type: Domain

This entry includes translation machinery-associated protein 22 (Tma22) from yeasts and density-regulated protein (DENR) from animals. DENR may be involved in the translation of target mRNAs by scanning and recognition of the initiation codon . DENR and MCT-1 form a heterodimer, which binds to the ribosome and is involved in unconventional translation initiation, reinitiation, and recycling .

This entry represents the C-terminal domain, which shows an eIF1-like fold (SUI1 in yeast). It is structurally similar to the canonical translation initiation factor eIF1, essential for initiation codon selection and scanning. It is involved in RNA binding .
ECSIT, N-terminal (ECSIT_N)
Type: Domain

This is the N-terminal helical domain which adopts a TPR-like structure.

Activation of NF-kappaB as a consequence of signalling through the Toll and IL-1 receptors is a major element of innate immune responses. ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway) plays an important role in signalling to NF-kappaB, functioning as an adapter protein of the Toll-like and IL-1 receptor signalling pathway and an intermediary in the signalling pathways between TRAF-6 and MEKK-1 . It is part of the MCIA (mitochondrial complex I intermediate assembly) complex, involved in the assembly of mitochondrial complex I .
Protease Do-like, PDZ domain superfamily (DEGP_PDZ_sf)
Type: Homologous_superfamily

This entry contains the second PDZ domain from serine protease Do-like proteins such as DEGP2/9 . This domain is involved in cage assembly.

This entry also includes DegP homologue from Plasmodium falciparum, a serine protease that also acts as a protein chaperone . It plays a role in the parasite development in host erythrocytes possibly by protecting it against thermal and oxidative stresses.
PA domain superfamily (PA_dom_sf)
Type: Homologous_superfamily

The PA (Protease associated) domain is found as an insert domain in diverse proteases, which include the MEROPS peptidase families A22B, M28, and S8A . The PA domain is also found in some plant vacuolar sorting receptors and members of the RZF family, including

. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors .
Homogentisate 1,2-dioxygenase, C-terminal domain (HgmA_C)
Type: Domain

Alkaptonuria (AKU), a rare hereditary disorder, was the first disease to be interpreted as an inborn error of metabolism. The deficiency causes homogentisic aciduria, ochronosis, and arthritis. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGD) (

), the enzyme that mediates the conversion of homogentisate to maleylacetoacetate, a step in the catabolism of both tyrosine and phenylalanine. The structure of this protein shows that the enzyme forms a hexamer arrangement comprised of a dimer of trimers. The active site iron ion is coordinated near the interface between the trimers .

This group of proteins includes human HDG and homologues from eukaryotes, bacteria and some archaeal species.

This entry represents the C-terminal active site domain of HGD.
Homogentisate 1,2-dioxygenase, N-terminal domain (HgmA_N)
Type: Domain

Alkaptonuria (AKU), a rare hereditary disorder, was the first disease to be interpreted as an inborn error of metabolism. The deficiency causes homogentisic aciduria, ochronosis, and arthritis. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGD) (

), the enzyme that mediates the conversion of homogentisate to maleylacetoacetate, a step in the catabolism of both tyrosine and phenylalanine. The structure of this protein shows that the enzyme forms a hexamer arrangement comprised of a dimer of trimers. The active site iron ion is coordinated near the interface between the trimers .

This group of proteins includes human HDG and homologues from eukaryotes, bacteria and some archaeal species.

This entry represents the N-terminal domain of HGD, which forms a jelly roll of β-strands .
Phage terminase large subunit GpA, ATPase domain (GpA_ATPase)
Type: Domain

This entry consists of several phage terminase large subunit proteins, including GpA (also known as TerL) from Bacteriophage lambda and from Enterobacteria phage P21, as well as related sequences from several bacterial species. The DNA packaging enzyme of Bacteriophage lambda, terminase, is a heteromultimer composed of a small subunit, gpNu1 involved in DNA recognition, and a large subunit, gpA involved in late stages of packaging, products of the Nu1 and A genes, respectively. Terminase is involved in the site-specific binding and cutting of the DNA in the initial stages of packaging. This large subunit is an ATPase required for viral DNA translocation into empty capsids and also acts as an endonuclease that cuts the viral genome from the concetamer to initiate and to end the packaging reaction .

This entry represents the N-terminal domain, which shows DNA translocase (packaging) and ATPase activities .
Terminase large subunit GpA, endonuclease domain (GpA_endonuclease)
Type: Domain

This entry consists of several phage terminase large subunit proteins, including GpA (also known as TerL) from Bacteriophage lambda and from Enterobacteria phage P21, as well as related sequences from several bacterial species. The DNA packaging enzyme of Bacteriophage lambda, terminase, is a heteromultimer composed of a small subunit, gpNu1 involved in DNA recognition, and a large subunit, gpA involved in late stages of packaging, products of the Nu1 and A genes, respectively. Terminase is involved in the site-specific binding and cutting of the DNA in the initial stages of packaging. This large subunit is an ATPase required for viral DNA translocation into empty capsids and also acts as an endonuclease that cuts the viral genome from the concetamer to initiate and to end the packaging reaction .

This entry represents the C-terminal domain, which shows DNA maturation (nuclease/helicase) catalytic activity .
Sec7/BIG1-like, C-terminal domain (Sec7/BIG1-like_C)
Type: Domain

This is the C-terminal domain of Sec7 and BIG1-like proteins (brefeldin A-inhibited guanine nucleotide-exchange protein). In Sec7, it has been described as HDS4 (homology downstream of Sec7) which mediates Sec7 dimerization .
Phosphomannose isomerase type I, C-terminal domain (PMI_typeI_C)
Type: Domain

This entry represents the C-terminal domain of Phosphomannose isomerase type I enzymes (also known as Mannose-6-phosphate isomerases), which are involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. This domain contains antiparallel β-strands in an extended jelly roll topology with short loops connecting the strands .
Phosphomannose isomerase type I, catalytic domain (PMI_typeI_cat)
Type: Domain

This entry represents the catalytic domain of Phosphomannose isomerase type I enzymes (also known as Mannose-6-phosphate isomerases), which are involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. This domain contains a zinc-binding site. It is composed of β-strands connected by long loops in a jelly roll conformation .
Phosphomannose isomerase type I, helical insertion domain (PMI_typeI_hel)
Type: Domain

This entry represents the α-helical insertion domain of Phosphomannose isomerase type I enzymes (also known as Mannose-6-phosphate isomerases), which are involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. The helices in this domain are packed closely, connected by short turns and loops. It packs against the catalytic domain, interrupting it .
Capsule biosynthesis GfcC-like, N-terminal (Caps_syn_GfcC_N)
Type: Domain

Many bacteria are covered in a layer of surface-associated polysaccharide called the capsule. These capsules can be divided into four groups depending upon the organisation of genes responsible for capsule assembly, the assembly pathway and regulation . This family plays a role in group 4 capsule biosynthesis . These proteins have a β-grasp fold . Two β-grasp domains, D2 and D3, are arranged in tandem. There is a C-terminal amphipathic helix which packs against D3. A helical hairpin insert in D2 binds to D3 and constrains its position, a conserved arginine residue at the end of this hairpin is essential for structural integrity . This entry represents D2 domain found at the N-terminal .
Protein UNC80, C-terminal (UNC80_C)
Type: Domain

This entry represents the C-terminal domain of protein UNC80 from eukaryotes, a component of the NALCN sodium channel complex. NALC is a cation voltage-independent channel activated by substance P, neurotensin, acetylcholine and noradrenaline that controls neuronal excitability. UNC80 forms a complex with UNC79 and both are key regulators of the channel and required for the proper expression and axonal localisation of NALCN. UNC80 is required for NALCN control by GPCRs and essential for its sensitivity to extracellular calcium. This protein acts as a scaffold for Src family of tyrosine kinases (SFK) and UNC-79 to mediate interaction with NALCN .
Terminase large subunit-like, ATPase domain (TerL_ATPase)
Type: Domain

Terminase large subunit (TerL) from bacteriophages and evolutionarily related viruses, is an important component of the DNA packing machinery and comprises an ATPase domain, which powers DNA translocation and a nuclease domain that cuts concatemeric DNA . TerL forms pentamers in which the ATPase domains form a ring distal to the capsid. This is the ATPase domain which contains a C-terminal subdomain that sits above the ATPase active site, called the "Lid subdomain" with reference to analogous lid subdomains found in other ATPases . It contains a hydrophobic patch (Trp and Tyr residues) that mediates critical interactions in the interface between adjacent ATPase subunits and assists the positioning of the arginine finger residue that catalyses ATP hydrolysis .
Terminase large subunit-like, endonuclease domain (TerL_nuclease)
Type: Domain

This is the endonuclease domain of bacteriophage Terminase large subunit TerL , a key component of the DNA packing machinery in tailed bacteriophages and related viruses. TerL comprises a N-terminal ATPase domain (

) which powers the DNA translocation and this C-terminal endonuclease domain that cuts concatemeric DNA first in the initiation phase in a sequence specific site and later in the completion stage of the DNA packaging process when the capsid is full . Cryo-EM studies indicate that TerL forms a pentamer that binds to a dodecameric assembly called portal and attaches to the capsid. It has been proposed that nuclease domains form a radially arranged ring that is proximal to portal, playing a key role in pentamer assembly . This nuclease domain has a RNAse H-like fold and it has been proposed to utilise a two-metal catalysis mechanism like in other RNAse H-like endonucleases such as RNase H, transposases, retroviral integrases and RuvC Holliday junction resolvases .

This domain is also found in uncharacterised proteins encoded by bacterial prophages, including YmfN from Escherichia coli.
Envelope glycoprotein E, N-terminal (Herpes_gE_N)
Type: Domain

This entry represents the the N-terminal domain of Glycoprotein E (gE) from herpesvirus. This protein forms a complex with glycoprotein I (gI), functioning as an immunoglobulin G (IgG) Fc binding protein. gE is involved in virus spread but is not essential for propagation. This domain interacts with gI .
SWI/SNF and RSC complexes subunit Ssr4, C-terminal (SWI-SNF_Ssr4_C)
Type: Domain

This entry represents the C-terminal domain of Ssr4 (SWI/SNF and RSC complexes subunit ssr4), an essential component of the chromatin-remodelling SWI/SNF and RSC (remodelling the structure of chromatin) complexes found in S. pombe . This domain contains a conserved RYxxxHEWMEEI/V motif. RSC is involved in transcription regulation and nucleosome positioning which controls, particularly, membrane and organelle development genes. The ATP-dependent chromatin remodelling complex SWI/SNF is required for the positive and negative regulation of gene expression of a large number of genes through the regulation of nucleosome remodelling.
BLOC-1-related complex subunit 6, C-terminal helix (BORCS6_C)
Type: Domain

This entry represents a domain found in proteins conserved from nematodes to humans. Members include BORCS6 (BLOC-1-related complex subunit 6) also known as Lyspersin (lysosome-dispersing protein) or C17orf59. It constitutes sub-unit 6 of the BORC complex (BLOC-one-related complex). BORC is a multisubunit complex that regulates the positioning of lysosomes at the cell periphery, and consequently affects cell migration. BORC associates with the lysosomal membrane, where it functions to recruit the small GTPase Arl8. This initiates a series of interactions that promote the microtubule-guided transport of lysosomes toward the cell periphery . This domain is located at the C-terminal end of most proteins and forms an α- helix according to structure predictions.
Borealin, C-terminal (Borealin_C)
Type: Domain

The chromosomal passenger complex of Aurora B kinase, INCENP, and Survivin has essential regulatory roles at centromeres and the central spindle in mitosis. Borealin is also a member of the complex . Approximately half of Aurora B in mitotic cells is complexed with INCENP, Borealin, and Survivin. Depletion of Borealin by RNA interference delays mitotic progression and results in kinetochore-spindle mis-attachments and an increase in bipolar spindles associated with ectopic asters . This is the C-terminal dimerisation domain of borealin .
PHL domain (PHL_dom)
Type: Domain

This presumed domain is found in Protein PHYTOCHROME-DEPENDENT LATE-FLOWERING (PHL,

). PHL is involved in the phytochrome B-dependent regulation of flowering .
Spt20-like, SEP domain (Spt20-like_SEP)
Type: Domain

This entry represents the SEP domain found in Spt20 from yeast and human . This domain interacts with LisH motif helices of Taf5 .

This entry represents the Spt20 transcription factors in eukaryote organisms. The Spt20 protein is a subunit of the SAGA (Spt-Ada-Gcn5-acetyltransferase) complex, a large multiprotein complex involved in transcriptional regulation. In yeast, Spt20 plays a crucial role in maintaining the structural integrity of the SAGA complex, as no intact SAGA complex could be purified in Spt20 deletion strains. It is involved in chromatin organisation, histone acetylation, and IRE1-mediated unfolded protein response . The human homologue of Spt20 (hSPT20) has been identified as a bona fide subunit of the human SAGA complex and is required for its integrity . Functionally, Spt20 has been shown to participate in the regulation of specific genes. In yeast, it is required for the transcriptional elongation of PDR5 and the activation of seripauperin genes upon hypoxic stress exposure . In human cells, hSPT20 and other hSAGA subunits are specifically recruited to genes induced by endoplasmic reticulum (ER) stress .
S-adenosyl-l-methionine hydroxide adenosyltransferase, N-terminal domain (SAM_HAT_N)
Type: Domain

The S-adenosyl-L-methionine (SAM) hydroxide adenosyltransferase family groups several fluorinase and chlorinase enzymes whose common feature is that they mediate nucleophilic reactions of their respective halide ions to the C-5' carbon of SAM . These enzymes utilise a rigorously conserved amino acid side chain triad (Asp-Arg-His) which may have a role in activating water to hydroxide ion. Structural studies indicate that the protein is a homotrimer, with each monomer being composed of N- and C-terminal domains . The N-terminal domain has a central seven-stranded β-sheet, which combines parallel and antiparallel strands sandwiched between α-helices. The C-terminal domain forms a β-barrel with a greek-key topology. SAM is bound at the interface between the C-terminal domain of one monomer and the N-terminal domain of the neighbouring monomer, with a total of three molecules bound by the trimer. This group of proteins, which are predominantly found in prokaryotes, used to be known as DUF62 .

This entry represents the N-terminal domain of these enzymes.
S-adenosyl-l-methionine hydroxide adenosyltransferase, C-terminal domain (SAM_HAT_C)
Type: Domain

The S-adenosyl-L-methionine (SAM) hydroxide adenosyltransferase family groups several fluorinase and chlorinase enzymes whose common feature is that they mediate nucleophilic reactions of their respective halide ions to the C-5' carbon of SAM . These enzymes utilise a rigorously conserved amino acid side chain triad (Asp-Arg-His) which may have a role in activating water to hydroxide ion. Structural studies indicate that the protein is a homotrimer, with each monomer being composed of N- and C-terminal domains . The N-terminal domain has a central seven-stranded β-sheet, which combines parallel and antiparallel strands sandwiched between α-helices. The C-terminal domain forms a β-barrel with a greek-key topology. SAM is bound at the interface between the C-terminal domain of one monomer and the N-terminal domain of the neighbouring monomer, with a total of three molecules bound by the trimer. This group of proteins, which are predominantly found in prokaryotes, used to be known as DUF62 .

This entry represents the C-terminal domain of these enzymes.
Integrator complex subunit 14, C-terminal (IntS14_C)
Type: Domain

This entry represents the C-terminal α-helical domain of Integrator complex subunit 14 (IntS14) , a component of the integrator complex which is involved in the transcription of small nuclear RNAs (snRNA) and their 3'-box dependent processing. This complex is also involved in the 3'-end processing of the U7 snRNA, and the spliceosomal snRNAs U1 and U5 . IntS14 interacts with IntS13; both of them consist of an N-terminal VWA domain (

) followed by a central β-barrel domain (

) and a C-terminal α-helical domain, which are connected through a linker devoid of secondary structure elements. This domain contribute to binding by packing against the β-barrel of IntS13 .