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- PDB-9dw6: Crystal structure of SARS-CoV-2 main protease (Mpro) C145A mutant... -

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Entry
Database: PDB / ID: 9dw6
TitleCrystal structure of SARS-CoV-2 main protease (Mpro) C145A mutant in complex with peptide from human tRNA methyltransferase TRMT1
Components
  • 3C-like proteinase nsp5
  • tRNA (guanine(26)-N(2))-dimethyltransferase
KeywordsVIRAL PROTEIN / HYDROLASE / protease / host-virus protein interaction / RNA modifying enzyme
Function / homology
Function and homology information


tRNA (guanine26-N2)-dimethyltransferase / tRNA N2-guanine methylation / tRNA (guanine(10)-N2)-methyltransferase activity / tRNA (guanine(26)-N2)-dimethyltransferase activity / tRNA modification in the nucleus and cytosol / tRNA modification / protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity ...tRNA (guanine26-N2)-dimethyltransferase / tRNA N2-guanine methylation / tRNA (guanine(10)-N2)-methyltransferase activity / tRNA (guanine(26)-N2)-dimethyltransferase activity / tRNA modification in the nucleus and cytosol / tRNA modification / protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / tRNA binding / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / viral protein processing / host cell perinuclear region of cytoplasm / lyase activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / nucleoplasm / ATP binding / metal ion binding / nucleus / membrane
Similarity search - Function
tRNA methyltransferase, Trm1 / tRNA methyltransferase, Trm1, C-terminal / N2,N2-dimethylguanosine tRNA methyltransferase / Trm1 methyltransferase domain profile. / Zinc finger C-x8-C-x5-C-x3-H type (and similar) / Zinc finger, CCCH-type superfamily / zinc finger / Zinc finger, CCCH-type / Zinc finger C3H1-type profile. / RNA-dependent RNA polymerase, SARS-CoV-like ...tRNA methyltransferase, Trm1 / tRNA methyltransferase, Trm1, C-terminal / N2,N2-dimethylguanosine tRNA methyltransferase / Trm1 methyltransferase domain profile. / Zinc finger C-x8-C-x5-C-x3-H type (and similar) / Zinc finger, CCCH-type superfamily / zinc finger / Zinc finger, CCCH-type / Zinc finger C3H1-type profile. / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Carbamoyl-phosphate synthase subdomain signature 2. / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / Betacoronavirus single-stranded poly(A) binding domain / NSP1, C-terminal domain, betacoronavirus / : / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus replicase NSP2, C-terminal / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus
Similarity search - Domain/homology
Replicase polyprotein 1ab / tRNA (guanine(26)-N(2))-dimethyltransferase
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsD'Oliviera, A. / Mugridge, J.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143000 United States
Citation
Journal: Elife / Year: 2025
Title: Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease.
Authors: D'Oliviera, A. / Dai, X. / Mottaghinia, S. / Olson, S. / Geissler, E.P. / Etienne, L. / Zhang, Y. / Mugridge, J.S.
#1: Journal: Elife / Year: 2023
Title: Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease.
Authors: D'Oliviera, A. / Dai, X. / Mottaghinia, S. / Geissler, E.P. / Etienne, L. / Zhang, Y. / Mugridge, J.S.
#2: Journal: Biorxiv / Year: 2023
Title: Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease.
Authors: Da Oliviera, A. / Dai, X. / Mottaghinia, S. / Geissler, E.P. / Etienne, L. / Zhang, Y. / Mugridge, J.S.
History
DepositionOct 8, 2024Deposition site: RCSB / Processing site: RCSB
SupersessionOct 23, 2024ID: 8D35
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Database references / Category: citation / citation_author

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
C: tRNA (guanine(26)-N(2))-dimethyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,4878
Polymers69,2223
Non-polymers2665
Water6,413356
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4660 Å2
ΔGint-52 kcal/mol
Surface area25290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.787, 100.029, 103.252
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein / Protein/peptide , 2 types, 3 molecules ABC

#1: Protein 3C-like proteinase nsp5 / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


Mass: 33937.609 Da / Num. of mol.: 2 / Mutation: C145A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): Rosetta
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Protein/peptide tRNA (guanine(26)-N(2))-dimethyltransferase / tRNA 2 / 2-dimethylguanosine-26 methyltransferase / tRNA(guanine-26 / N(2)-N(2)) methyltransferase ...tRNA 2 / 2-dimethylguanosine-26 methyltransferase / tRNA(guanine-26 / N(2)-N(2)) methyltransferase / tRNA(m(2 / 2)G26)dimethyltransferase


Mass: 1346.534 Da / Num. of mol.: 1 / Fragment: UNP residues 526-536 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q9NXH9, tRNA (guanine26-N2)-dimethyltransferase

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Non-polymers , 4 types, 361 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 356 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.65 Å3/Da / Density % sol: 51.36 % / Description: Rhombohedral-shaped plates
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 20-21.5% PEG3350, 100 mM sodium chloride, diffraction-quality crystals obtained from seeding

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.920219 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.920219 Å / Relative weight: 1
ReflectionResolution: 1.9→29.34 Å / Num. obs: 55521 / % possible obs: 99.08 % / Redundancy: 13.8 % / Biso Wilson estimate: 26.94 Å2 / CC1/2: 0.997 / Net I/σ(I): 9.71
Reflection shellResolution: 1.9→1.968 Å / Redundancy: 14 % / Mean I/σ(I) obs: 1.47 / Num. unique obs: 5409 / CC1/2: 0.656 / % possible all: 98.34

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Processing

Software
NameVersionClassification
XDSJan 31, 2020data reduction
XDSJan 31, 2020data scaling
PHASER2.8.3phasing
PHENIX1.17.1_3660refinement
Coot0.8.9.1model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→29.34 Å / SU ML: 0.1972 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.6033
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2179 1987 3.6 %
Rwork0.1805 53646 -
obs0.1819 55515 98.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.4 Å2
Refinement stepCycle: LAST / Resolution: 1.9→29.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4719 0 15 356 5090
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00684833
X-RAY DIFFRACTIONf_angle_d0.8256564
X-RAY DIFFRACTIONf_chiral_restr0.054741
X-RAY DIFFRACTIONf_plane_restr0.0057852
X-RAY DIFFRACTIONf_dihedral_angle_d21.1021654
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.940.281320.26243579X-RAY DIFFRACTION93.48
1.94-20.27281370.24473777X-RAY DIFFRACTION98.34
2-2.060.27711410.22823776X-RAY DIFFRACTION98.59
2.06-2.120.29741440.22473782X-RAY DIFFRACTION98.84
2.12-2.20.24141310.20723785X-RAY DIFFRACTION98.89
2.2-2.290.22751540.20323806X-RAY DIFFRACTION99.12
2.29-2.390.24651370.1973795X-RAY DIFFRACTION99.27
2.39-2.520.24371440.18993853X-RAY DIFFRACTION98.91
2.52-2.670.23311420.18493812X-RAY DIFFRACTION99.55
2.67-2.880.2481480.17383850X-RAY DIFFRACTION99.35
2.88-3.170.2061420.1783875X-RAY DIFFRACTION99.6
3.17-3.630.21571450.16633899X-RAY DIFFRACTION99.7
3.63-4.570.171420.14663947X-RAY DIFFRACTION99.85
4.57-29.340.19411550.17294110X-RAY DIFFRACTION99.84
Refinement TLS params.Method: refined / Origin x: 2.70976352293 Å / Origin y: -2.80319390672 Å / Origin z: -16.6822728463 Å
111213212223313233
T0.141058257595 Å20.00541884892019 Å20.00504520836862 Å2-0.137403633299 Å20.0193780616604 Å2--0.160928211819 Å2
L0.0685906372401 °2-0.0411233354879 °2-0.0278774313034 °2-0.206699457361 °2-0.0650539498671 °2--0.510102903798 °2
S0.011514982593 Å °-0.00358069556761 Å °-0.0153911260834 Å °0.0168835830124 Å °-0.00534095616609 Å °0.0432197743127 Å °-0.00517670236837 Å °-0.0310290309205 Å °-1.29193984535E-7 Å °
Refinement TLS groupSelection details: all

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