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- PDB-8e1y: Crystal Structure of SARS-CoV-2 Main protease A193S mutant in com... -

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Entry
Database: PDB / ID: 8e1y
TitleCrystal Structure of SARS-CoV-2 Main protease A193S mutant in complex with Nirmatrelvir
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / Mpro / 3cl / covid / sars-cov-2 ensitrelvir / nirmatrelvir / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


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 ...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 / 5'-3' DNA helicase activity / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / SARS coronavirus main proteinase / host cell endosome / 3'-5'-RNA exonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host toll-like receptor signaling pathway / 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 / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / virus-mediated perturbation of host defense response / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent 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 / ATP binding / membrane
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / : / Coronavirus Nsp12 Interface domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / : / Coronavirus Nsp12 Interface domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2-O-methyltransferase / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 13, 1B domain, coronavirus / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) 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 / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / DNA2/NAM7 helicase-like, C-terminal / AAA domain / Lipocalin signature. / (+) 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 Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Coronavirus 3Ecto domain profile. / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus
Similarity search - Domain/homology
Chem-4WI / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsNoske, G.D. / Oliva, G. / Godoy, A.S.
Funding support Brazil, 1items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP)2013/07600-3 Brazil
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease.
Authors: Noske, G.D. / de Souza Silva, E. / de Godoy, M.O. / Dolci, I. / Fernandes, R.S. / Guido, R.V.C. / Sjo, P. / Oliva, G. / Godoy, A.S.
History
DepositionAug 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 22, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8426
Polymers67,6832
Non-polymers1,1594
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3250 Å2
ΔGint-11 kcal/mol
Surface area25460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.905, 103.925, 68.025
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 33841.547 Da / Num. of mol.: 2 / Mutation: A193S
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 (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-4WI / (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide / PF-07321332, bound form / nirmatrelvir, bound form / Paxlovid, bound form / Nirmatrelvir


Mass: 501.542 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H34F3N5O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antivirus, protease inhibitor*YM
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.63 Å3/Da / Density % sol: 53.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1 M MES pH 6.7, 5% DMSO, 8% PEG 4000 Cryo protected with 40% PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: LNLS SIRUS / Beamline: MANACA / Wavelength: 0.97718 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Apr 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97718 Å / Relative weight: 1
ReflectionResolution: 2.48→72.5 Å / Num. obs: 15497 / % possible obs: 59.5 % / Redundancy: 6.4 % / CC1/2: 0.965 / Net I/σ(I): 3.9
Reflection shellResolution: 2.48→2.57 Å / Num. unique obs: 86 / CC1/2: 0.575

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7mbg

7mbg


Resolution: 2.48→72.5 Å / Cor.coef. Fo:Fc: 0.904 / Cor.coef. Fo:Fc free: 0.829 / SU B: 15.089 / SU ML: 0.321 / Cross valid method: FREE R-VALUE / ESU R Free: 0.466
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2723 765 4.942 %
Rwork0.2166 14716 -
all0.219 --
obs-15481 59.506 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 31.165 Å2
Baniso -1Baniso -2Baniso -3
1-0.386 Å2-0 Å20 Å2
2---0.336 Å2-0 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 2.48→72.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4669 0 78 31 4778
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134861
X-RAY DIFFRACTIONr_bond_other_d0.0030.0154508
X-RAY DIFFRACTIONr_angle_refined_deg1.4871.6446624
X-RAY DIFFRACTIONr_angle_other_deg1.3011.57610356
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5695603
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.67722.724246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.15615768
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9761522
X-RAY DIFFRACTIONr_chiral_restr0.0570.2640
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025579
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021145
X-RAY DIFFRACTIONr_nbd_refined0.20.2890
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2080.24341
X-RAY DIFFRACTIONr_nbtor_refined0.1660.22365
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.080.22292
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1970.2125
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.4140.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.5040.228
X-RAY DIFFRACTIONr_nbd_other0.5380.288
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1470.23
X-RAY DIFFRACTIONr_mcbond_it1.7813.2262415
X-RAY DIFFRACTIONr_mcbond_other1.7813.2252414
X-RAY DIFFRACTIONr_mcangle_it3.1754.8273014
X-RAY DIFFRACTIONr_mcangle_other3.1744.8283015
X-RAY DIFFRACTIONr_scbond_it1.6383.482446
X-RAY DIFFRACTIONr_scbond_other1.6373.4812447
X-RAY DIFFRACTIONr_scangle_it2.8965.1623603
X-RAY DIFFRACTIONr_scangle_other2.8965.1633604
X-RAY DIFFRACTIONr_lrange_it5.64738.055128
X-RAY DIFFRACTIONr_lrange_other5.64738.0595128
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.48-2.5440.41240.40944X-RAY DIFFRACTION2.5505
2.544-2.6140.28760.29120X-RAY DIFFRACTION6.859
2.614-2.690.43360.341145X-RAY DIFFRACTION8.4076
2.69-2.7720.36170.336297X-RAY DIFFRACTION18.1084
2.772-2.8630.335270.306596X-RAY DIFFRACTION36.561
2.863-2.9640.376360.295847X-RAY DIFFRACTION52.685
2.964-3.0750.333410.272938X-RAY DIFFRACTION62.8773
3.075-3.2010.302620.2671005X-RAY DIFFRACTION69.421
3.201-3.3430.288530.2441078X-RAY DIFFRACTION77.5189
3.343-3.5060.288650.2411079X-RAY DIFFRACTION82.066
3.506-3.6950.341620.2361107X-RAY DIFFRACTION86.5926
3.695-3.9190.239620.2261092X-RAY DIFFRACTION90.7947
3.919-4.1890.222670.1881086X-RAY DIFFRACTION95.2893
4.189-4.5240.257580.1611041X-RAY DIFFRACTION98.125
4.524-4.9550.216410.162987X-RAY DIFFRACTION98.5618
4.955-5.5390.233480.187886X-RAY DIFFRACTION98.4194
5.539-6.3930.25400.24796X-RAY DIFFRACTION99.2874
6.393-7.8220.417300.207692X-RAY DIFFRACTION99.5862
7.822-11.030.267290.16551X-RAY DIFFRACTION99.4854

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