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Yorodumi- PDB-8bwu: Crystal structure of SARS-CoV-2 nsp14 methyltransferase domain in... -
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-Basic information
Entry | Database: PDB / ID: 8bwu | ||||||
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Title | Crystal structure of SARS-CoV-2 nsp14 methyltransferase domain in complex with the SS148 inhibitor | ||||||
Components | Transcription factor ETV6,Proofreading exoribonuclease nsp14 | ||||||
Keywords | VIRAL PROTEIN / viral / SARS-CoV-2 / covid-19 / methyltransferase / RNA cap / inhibitor / SS148 | ||||||
Function / homology | Function and homology information Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / mesenchymal cell apoptotic process / vitellogenesis / hematopoietic stem cell proliferation / Signaling by FLT3 fusion proteins / neurogenesis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters ...Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / mesenchymal cell apoptotic process / vitellogenesis / hematopoietic stem cell proliferation / Signaling by FLT3 fusion proteins / neurogenesis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / TRAF3-dependent IRF activation pathway / Replication of the SARS-CoV-2 genome / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 5'-3' DNA helicase activity / SARS coronavirus main proteinase / host cell endosome / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / SARS-CoV-2 modulates host translation machinery / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / mRNA (guanine-N7)-methyltransferase / host cell Golgi apparatus / methyltransferase cap1 / DNA-binding transcription activator activity, RNA polymerase II-specific / symbiont-mediated perturbation of host ubiquitin-like protein modification / mRNA (nucleoside-2'-O-)-methyltransferase activity / DNA helicase / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / viral protein processing / lyase activity / DNA-binding transcription factor activity, RNA polymerase II-specific / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / induction by virus of host autophagy / copper ion binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / RNA-directed RNA polymerase / DNA-binding transcription factor activity / protein domain specific binding / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / DNA-templated transcription / lipid binding / host cell nucleus / chromatin / nucleolus / regulation of transcription by RNA polymerase II / SARS-CoV-2 activates/modulates innate and adaptive immune responses / negative regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / nucleus / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | Severe acute respiratory syndrome coronavirus 2 | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å | ||||||
Authors | Konkolova, E. / Klima, M. / Boura, E. / Jin, J. / Kaniskan, H.U. / Han, Y. / Vedadi, M. | ||||||
Funding support | 1items
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Citation | Journal: Digit Discov / Year: 2024 Title: Application of established computational techniques to identify potential SARS-CoV-2 Nsp14-MTase inhibitors in low data regimes Authors: Nigam, A. / Hurley, M.F.D. / Li, F. / Konkolova, E. / Klima, M. / Trylcova, J. / Pollice, R. / Cinaroglu, S.S. / Levin-Konigsberg, R. / Handjaya, J. / Schapira, M. / Chau, I. / Perveen, S. / ...Authors: Nigam, A. / Hurley, M.F.D. / Li, F. / Konkolova, E. / Klima, M. / Trylcova, J. / Pollice, R. / Cinaroglu, S.S. / Levin-Konigsberg, R. / Handjaya, J. / Schapira, M. / Chau, I. / Perveen, S. / Ng, H.L. / Kaniskan, H.U. / Han, Y. / Singh, S. / Gorgulla, C. / Kundaje, A. / Jin, J. / Voelz, V.A. / Weber, J. / Nencka, R. / Boura, E. / Vedadi, M. / Aspuru-Guzik, A. #1: Journal: Biorxiv / Year: 2024 Title: Drug Discovery in Low Data Regimes: Leveraging a Computational Pipeline for the Discovery of Novel SARS-CoV-2 Nsp14-MTase Inhibitors. Authors: Nigam, A. / Hurley, M.F.D. / Li, F. / Konkolova, E. / Klima, M. / Trylcova, J. / Pollice, R. / Cinaroglu, S.S. / Levin-Konigsberg, R. / Handjaya, J. / Schapira, M. / Chau, I. / Perveen, S. / ...Authors: Nigam, A. / Hurley, M.F.D. / Li, F. / Konkolova, E. / Klima, M. / Trylcova, J. / Pollice, R. / Cinaroglu, S.S. / Levin-Konigsberg, R. / Handjaya, J. / Schapira, M. / Chau, I. / Perveen, S. / Ng, H.L. / Umit Kaniskan, H. / Han, Y. / Singh, S. / Gorgulla, C. / Kundaje, A. / Jin, J. / Voelz, V.A. / Weber, J. / Nencka, R. / Boura, E. / Vedadi, M. / Aspuru-Guzik, A. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8bwu.cif.gz | 85.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8bwu.ent.gz | 50.4 KB | Display | PDB format |
PDBx/mmJSON format | 8bwu.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8bwu_validation.pdf.gz | 722.8 KB | Display | wwPDB validaton report |
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Full document | 8bwu_full_validation.pdf.gz | 723.4 KB | Display | |
Data in XML | 8bwu_validation.xml.gz | 11.4 KB | Display | |
Data in CIF | 8bwu_validation.cif.gz | 14.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/bw/8bwu ftp://data.pdbj.org/pub/pdb/validation_reports/bw/8bwu | HTTPS FTP |
-Related structure data
Similar structure data | Similarity search - Function & homologyF&H Search |
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-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 35526.422 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: SARS-CoV-2 nsp14 methyltransferase domain (residues 300-527) is N-terminally fused to a crystallization tag TELSAM via a Pro-Ala-Ala tripeptide linker.,SARS-CoV-2 nsp14 methyltransferase ...Details: SARS-CoV-2 nsp14 methyltransferase domain (residues 300-527) is N-terminally fused to a crystallization tag TELSAM via a Pro-Ala-Ala tripeptide linker.,SARS-CoV-2 nsp14 methyltransferase domain (residues 300-527) is N-terminally fused to a crystallization tag TELSAM via a Pro-Ala-Ala tripeptide linker. Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2 Gene: ETV6, TEL, TEL1, rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria) References: UniProt: P41212, UniProt: P0DTD1, Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters |
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#2: Chemical | ChemComp-6NR / ( |
#3: Chemical | ChemComp-ZN / |
#4: Water | ChemComp-HOH / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.36 Å3/Da / Density % sol: 47.92 % |
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Crystal grow | Temperature: 291 K / Method: vapor diffusion, sitting drop Details: 100 mM bicine/Trizma pH 8.5; 10% w/v PEG 20.000, 20% v/v PEG MME 550; 20 mM D-glucose, 20 mM D-mannose, 20 mM D-galactose, 20 mM L-fucose, 20 mM D-xylose, 20 mM N-acetyl-D-glucosamine |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 16, 2022 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9184 Å / Relative weight: 1 |
Reflection | Resolution: 2.36→47.33 Å / Num. obs: 13850 / % possible obs: 99.46 % / Redundancy: 19.9 % / Biso Wilson estimate: 46.03 Å2 / CC1/2: 0.995 / CC star: 0.999 / Rmerge(I) obs: 0.3783 / Rpim(I) all: 0.08633 / Rrim(I) all: 0.3881 / Net I/σ(I): 7.63 |
Reflection shell | Resolution: 2.36→2.444 Å / Redundancy: 15.9 % / Rmerge(I) obs: 3.603 / Mean I/σ(I) obs: 0.54 / Num. unique obs: 1383 / CC1/2: 0.422 / CC star: 0.77 / Rpim(I) all: 0.9254 / Rrim(I) all: 3.722 / % possible all: 98.19 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.36→47.33 Å / SU ML: 0.3029 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 31.7285 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 56.74 Å2 | ||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.36→47.33 Å
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Refine LS restraints |
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LS refinement shell |
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