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- PDB-7xb4: Crystal structure of SARS-Cov-2 main protease D48N mutant in comp... -

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Basic information

Entry
Database: PDB / ID: 7xb4
TitleCrystal structure of SARS-Cov-2 main protease D48N mutant in complex with PF07321332
ComponentsReplicase polyprotein 1a
KeywordsVIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


viral genome replication / methyltransferase 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 / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase 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 / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 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 cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / endonuclease activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / methylation / 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 / regulation of autophagy / viral protein processing / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Peptidase family C16 domain profile. / : / : / Coronavirus replicase NSP7 / Coronavirus 3Ecto 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. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-4WI / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsHu, X.H. / Li, J. / Zhang, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Viruses / Year: 2023
Title: Structural Basis for the Inhibition of SARS-CoV-2 M pro D48N Mutant by Shikonin and PF-07321332.
Authors: Zhao, Z. / Zhu, Q. / Zhou, X. / Li, W. / Yin, X. / Li, J.
History
DepositionMar 20, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 2, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Replicase polyprotein 1a
B: Replicase polyprotein 1a
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6524
Polymers67,6492
Non-polymers1,0032
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-8 kcal/mol
Surface area25080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.152, 102.656, 103.355
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

#1: Protein Replicase polyprotein 1a / pp1a / ORF1a polyprotein


Mass: 33824.562 Da / Num. of mol.: 2 / Mutation: D48N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P0DTC1
#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


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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.67 Å3/Da / Density % sol: 53.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M HEPES 7.5, 20% PEG 10000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.979183 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Mar 11, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979183 Å / Relative weight: 1
ReflectionResolution: 2.07→72.83 Å / Num. obs: 42254 / % possible obs: 94.4 % / Redundancy: 10.3 % / Biso Wilson estimate: 31.4738586135 Å2 / Rmerge(I) obs: 0.037 / Net I/σ(I): 15.7
Reflection shellResolution: 2.07→2.2 Å / Rmerge(I) obs: 0.861 / Num. unique obs: 42172

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7DQZ

7dqz


Resolution: 2.07→56.9175 Å / SU ML: 0.250812049434 / Cross valid method: NONE / σ(F): 1.34493102168 / Phase error: 25.660834693
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.240304093051 3783 4.7253831645 %
Rwork0.21094691164 76274 -
obs0.212352500906 42172 94.3345313144 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.3047455827 Å2
Refinement stepCycle: LAST / Resolution: 2.07→56.9175 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4388 0 70 56 4514
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007605866579634563
X-RAY DIFFRACTIONf_angle_d0.934365449516245
X-RAY DIFFRACTIONf_chiral_restr0.0505219945251734
X-RAY DIFFRACTIONf_plane_restr0.00631824660968801
X-RAY DIFFRACTIONf_dihedral_angle_d6.981432052372740
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.07-2.10040.3162318853091500.2938691486932963X-RAY DIFFRACTION99.7756410256
2.1004-2.1280.3539962809791460.2757603301343034X-RAY DIFFRACTION99.9685633449
2.128-2.15710.2930839003471500.2655014375412962X-RAY DIFFRACTION99.9036918138
2.1571-2.1880.258728694441530.2523967142282971X-RAY DIFFRACTION99.8721227621
2.188-2.22060.2723744813681570.2464211294083009X-RAY DIFFRACTION99.9368686869
2.2206-2.25530.296093881836820.2562470680171788X-RAY DIFFRACTION94.3015632879
2.2553-2.29230.2854505401611060.252539695632172X-RAY DIFFRACTION99.7373029772
2.2923-2.33180.2606077245481460.2406088186473019X-RAY DIFFRACTION99.9368487528
2.3318-2.37420.2670090729081560.2467957166652970X-RAY DIFFRACTION100
2.3742-2.41990.2551889268421490.2289717270682981X-RAY DIFFRACTION100
2.4199-2.46930.3018176379581400.2382878886443004X-RAY DIFFRACTION99.9682034976
2.4693-2.5230.2516931248861560.2350436324573024X-RAY DIFFRACTION100
2.523-2.58170.333876115151360.2353973440232967X-RAY DIFFRACTION99.9355877617
2.5817-2.64620.2897576160631500.2307209243332976X-RAY DIFFRACTION100
2.6462-2.71780.349623425518950.2323097312481926X-RAY DIFFRACTION63.9759417537
2.7178-2.79780.277737314561520.2409710401672995X-RAY DIFFRACTION99.9047619048
2.7978-2.88810.2642083494541560.239877670852978X-RAY DIFFRACTION99.9681020734
2.8881-2.99130.2830959995361470.2300664921693005X-RAY DIFFRACTION100
2.9913-3.1110.2533172377011560.2187599329092994X-RAY DIFFRACTION99.9365482234
3.111-3.25260.2535018227051430.2302043465282995X-RAY DIFFRACTION99.9681427206
3.2526-3.42410.2324542042811450.2246383558283026X-RAY DIFFRACTION99.9684741488
3.4241-3.63860.2263194575881180.2153025410862406X-RAY DIFFRACTION80.9233728759
3.6386-3.91940.2271347960461000.1887075557332152X-RAY DIFFRACTION72.133247918
3.9194-4.31370.1987118810641450.1680210969043001X-RAY DIFFRACTION100
4.3137-4.93760.1767538594381480.1632955926532997X-RAY DIFFRACTION99.9364474102
4.9376-6.21970.1981699840591540.1851991608952996X-RAY DIFFRACTION100
6.2197-56.91750.1978646363971470.1750796743592963X-RAY DIFFRACTION99.1709183673

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