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- PDB-8hvo: Crystal structure of SARS-Cov-2 main protease V186F mutant in com... -

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Entry
Database: PDB / ID: 8hvo
TitleCrystal structure of SARS-Cov-2 main protease V186F mutant in complex with PF07321332
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN/INHIBITOR / 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 / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / methylation / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / host cell perinuclear region of cytoplasm / single-stranded RNA binding / host cell endoplasmic reticulum membrane / viral protein processing / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / lipid binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
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. ...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 / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / 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 / : / Coronavirus 3Ecto domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / : / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus replicase NSP7 / Peptidase family C16 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 Nsp4 C-terminal (Nsp4C) 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 main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
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: 1.65 Å
AuthorsZou, X.F. / Zhang, J. / Li, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Crystal structure of SARS-Cov-2 main protease V186F mutant in complex with PF07321332
Authors: Zou, X.F. / Zhang, J. / Li, J.
History
DepositionDec 27, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 27, 2023Provider: repository / Type: Initial release

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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)67,3974
Polymers66,3942
Non-polymers1,0032
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint-5 kcal/mol
Surface area24860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.740, 99.191, 59.513
Angle α, β, γ (deg.)90.000, 108.822, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 33196.875 Da / Num. of mol.: 2
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, 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


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.: 91 / 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: 2.35 Å3/Da / Density % sol: 47.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2M Na2SO4, 20%PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Sep 3, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.65→56.33 Å / Num. obs: 73323 / % possible obs: 99.8 % / Redundancy: 9.3 % / Biso Wilson estimate: 23.5020587753 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 12.7
Reflection shellResolution: 1.65→1.74 Å / Rmerge(I) obs: 0.648 / Num. unique obs: 10679

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→56.33 Å / SU ML: 0.226991657002 / Cross valid method: FREE R-VALUE / σ(F): 1.3364812449 / Phase error: 29.7701457557
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.258046435248 3590 4.939120864 %
Rwork0.226307930233 69095 -
obs0.22787648399 72685 98.9948653692 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.367438206 Å2
Refinement stepCycle: LAST / Resolution: 1.65→56.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4480 0 70 91 4641
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008214552371324656
X-RAY DIFFRACTIONf_angle_d1.286500310356366
X-RAY DIFFRACTIONf_chiral_restr0.281722596991739
X-RAY DIFFRACTIONf_plane_restr0.0063621686171823
X-RAY DIFFRACTIONf_dihedral_angle_d8.952308284492802
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.67220.3135642062011470.2871269025972622X-RAY DIFFRACTION99.7478386167
1.6722-1.69510.3181440652361390.2650196595862670X-RAY DIFFRACTION99.6806245564
1.6951-1.71940.2860267859811330.2534837841212696X-RAY DIFFRACTION100
1.7194-1.7450.2946411302321380.2540358131192678X-RAY DIFFRACTION99.9645012425
1.745-1.77230.2989459808461600.2387549231492648X-RAY DIFFRACTION99.9644001424
1.7723-1.80130.2804004299341280.2413430003122727X-RAY DIFFRACTION99.9649859944
1.8013-1.83240.2819637074711240.2353976978682626X-RAY DIFFRACTION99.8910279695
1.8324-1.86570.2906610262191210.2480574409662757X-RAY DIFFRACTION99.8265695456
1.8657-1.90160.3160250873291140.2998709655352543X-RAY DIFFRACTION96.0245753524
1.9016-1.94040.4265204263241050.3725985368872538X-RAY DIFFRACTION94.0569395018
1.9404-1.98260.2876518914891350.2455958148792699X-RAY DIFFRACTION99.859055673
1.9826-2.02880.2769783384211500.2374275914872642X-RAY DIFFRACTION99.8569384835
2.0288-2.07950.2852566103821520.2497947562232649X-RAY DIFFRACTION99.7507122507
2.0795-2.13570.2751387079061550.2411598087472704X-RAY DIFFRACTION99.9300943726
2.1357-2.19860.2917948984481430.2424544418442661X-RAY DIFFRACTION99.7864768683
2.1986-2.26950.3758042256161210.316432540842432X-RAY DIFFRACTION91.4070891515
2.2695-2.35060.2943222113571410.2642391019172600X-RAY DIFFRACTION96.4461646728
2.3506-2.44480.2633307227271360.2469654380782681X-RAY DIFFRACTION99.7874601488
2.4448-2.5560.2856225717091490.2414518960552664X-RAY DIFFRACTION99.9644633973
2.556-2.69080.3139935981441450.2545868262652692X-RAY DIFFRACTION99.7538677918
2.6908-2.85940.250662436261530.250862211452655X-RAY DIFFRACTION99.7867803838
2.8594-3.08010.3140843897881270.2467139303412707X-RAY DIFFRACTION99.7887323944
3.0801-3.39010.2813642144791330.2394991665472680X-RAY DIFFRACTION99.6810772502
3.3901-3.88050.2646357204941350.2022240230892698X-RAY DIFFRACTION99.3338008415
3.8805-4.88860.1665780317981450.1621360731862701X-RAY DIFFRACTION99.9297752809
4.8886-56.330.1870989632871610.1692080874692725X-RAY DIFFRACTION99.6546961326

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