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- PDB-8und: X-ray Structure of SARS-CoV-2 main protease covalently bound to i... -

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Entry
Database: PDB / ID: 8und
TitleX-ray Structure of SARS-CoV-2 main protease covalently bound to inhibitor GRL-190-21 at 1.90 A.
ComponentsORF1a polyprotein
KeywordsVIRAL PROTEIN / main protease / 3c like protease / 3CLpro / Mpro / nirmatrelvir / inhibitor / COVID-19 / SARS-CoV-2 / Structural Genomics / Center for Structural Biology of Infectious Diseases / CSBID
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / symbiont-mediated degradation of host mRNA / 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 / symbiont-mediated perturbation of host ubiquitin-like protein modification / methylation ...host cell membrane / viral genome replication / methyltransferase activity / symbiont-mediated degradation of host mRNA / 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 / symbiont-mediated perturbation of host ubiquitin-like protein modification / methylation / single-stranded RNA binding / host cell perinuclear region of cytoplasm / 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 / 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 / Betacoronavirus Nsp3c-M 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 / 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 / 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 replicase NSP7 / Peptidase family C16 domain profile. / 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. / 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
: / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMesecar, A.D. / Lendy, E.K. / Ghosh, A.K. / Center for Structural Biology of Infectious Diseases (CSBID)
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93022C00035 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI158649 United States
CitationJournal: To Be Published
Title: X-ray Structure of SARS-CoV-2 main protease covalently bound to inhibitor GRL-190-21 at 1.90 A.
Authors: Mesecar, A.D. / Lendy, E.K. / Ghosh, A.K.
History
DepositionOct 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ORF1a polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3412
Polymers33,8261
Non-polymers5161
Water6,125340
1
A: ORF1a polyprotein
hetero molecules

A: ORF1a polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6824
Polymers67,6512
Non-polymers1,0312
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area3170 Å2
ΔGint-15 kcal/mol
Surface area25110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.848, 63.968, 105.240
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-630-

HOH

21A-828-

HOH

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Components

#1: Protein ORF1a polyprotein


Mass: 33825.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus
Gene: ORF1ab / Production host: Escherichia coli (E. coli) / References: UniProt: A0A8B1JK87
#2: Chemical ChemComp-X4N / (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide


Mass: 515.569 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H36F3N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.28 Å3/Da / Density % sol: 46.08 %
Crystal growTemperature: 279 K / Method: vapor diffusion, sitting drop / pH: 6
Details: Briefly, 1 uL of ~110 uM SARS-CoV-2 3CLpro in 25 mM HEPES pH 7.5, 2.5 mM DTT containing ~150 uM GRL-190-21 was mixed with 2 uL of reservoir solution which contained a constant concentration ...Details: Briefly, 1 uL of ~110 uM SARS-CoV-2 3CLpro in 25 mM HEPES pH 7.5, 2.5 mM DTT containing ~150 uM GRL-190-21 was mixed with 2 uL of reservoir solution which contained a constant concentration of 3 mM DTT, 50 mM MES pH 6.0, 1% MPD, and varying concentrations of PEG-10,000 and KCl.
Temp details: 4 C cold room

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Oct 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.9→35.08 Å / Num. obs: 25135 / % possible obs: 99.75 % / Redundancy: 9.5 % / Biso Wilson estimate: 20.18 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1174 / Rpim(I) all: 0.0389 / Rrim(I) all: 0.1239 / Net I/σ(I): 17.42
Reflection shellResolution: 1.9→1.968 Å / Redundancy: 9.3 % / Rmerge(I) obs: 0.8125 / Mean I/σ(I) obs: 3.18 / Num. unique obs: 2459 / CC1/2: 0.852 / CC star: 0.959 / Rpim(I) all: 0.2698 / Rrim(I) all: 0.8571 / % possible all: 99.43

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→35.08 Å / SU ML: 0.1707 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.5911
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2025 1257 5 %
Rwork0.1505 23873 -
obs0.1531 25130 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.85 Å2
Refinement stepCycle: LAST / Resolution: 1.9→35.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2368 0 36 340 2744
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01312525
X-RAY DIFFRACTIONf_angle_d1.1963448
X-RAY DIFFRACTIONf_chiral_restr0.199386
X-RAY DIFFRACTIONf_plane_restr0.035449
X-RAY DIFFRACTIONf_dihedral_angle_d9.9886354
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.970.26841360.19442567X-RAY DIFFRACTION98.69
1.97-2.060.22751360.17012611X-RAY DIFFRACTION99.67
2.06-2.170.21371380.15362605X-RAY DIFFRACTION99.82
2.17-2.310.21471380.15292627X-RAY DIFFRACTION99.78
2.31-2.490.21771380.15662622X-RAY DIFFRACTION99.89
2.49-2.740.18261400.15752655X-RAY DIFFRACTION99.86
2.74-3.130.20721400.1572661X-RAY DIFFRACTION99.96
3.13-3.940.22031410.13962695X-RAY DIFFRACTION99.93
3.95-35.080.16621500.13672830X-RAY DIFFRACTION99.67
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.444944293011.53837625261.609112053892.149134886041.075940503582.51887399553-0.02007312911950.0797898226044-0.186523453546-0.05090500221320.05575894757-0.02663028187640.1087670762740.03854364454310.006184941399330.09975824578540.02276278683070.0152746994260.0702961724357-0.0104183274240.100599562183-7.2323007512323.0532650319-36.386127685
22.31895390960.9180606145810.5666959170682.72784706389-1.488157111795.14073703056-0.1776441476420.142704621113-0.160481474792-0.1489039227940.2943190640040.3299608589060.485763435302-0.594261267472-0.1315378637040.267735978075-0.0551126810868-0.01045649876180.214779608967-0.05916074280430.266361371184-19.525826832812.4989995609-41.8676440433
31.689569450850.6738323222910.2945755461431.52086830986-0.4084058070623.95446389511-0.1219488057530.214346130517-0.326496411386-0.127735988429-0.00540613673037-0.1388878439840.2950849052520.4663340158730.1312769324090.1583169300660.05237288908520.07396913748860.171866486789-0.04266757526480.1945942495570.37185338644516.470537395-38.887368118
42.073921802250.4497140649141.432287998570.7857516799360.4442762797191.087548888530.0331641944604-0.0905587796192-0.1974807772140.0289128777847-0.03419714090140.02992181447770.124968306088-0.01525404599930.02803113412520.1112546758110.02020820626630.05110131969570.1245184866180.006873076385080.114783116683-4.3338085271319.1999180904-25.0400802147
52.877212724270.346056259110.2792633831612.963716817340.05557593499162.02635749245-0.0237634741512-0.433507252045-0.1621220891060.4174487522510.0543305304084-0.004843013391940.0818580413191-0.0439681368261-0.02141088488060.166250119350.043709741023-0.003524421116960.1960891366290.04868465091870.12207962394412.82708379520.7090855512-8.04860120047
60.00275983109248-0.0120082671398-0.07096627498810.05149957286720.3080282027681.85580447788-0.06456705202140.7181215447550.304086879236-0.6935738319780.1332936102940.0435610106586-0.207414242029-0.0831469946819-0.002435463220950.285069777225-0.0234977262119-0.007615347296910.4011865557810.08601544028850.20958338877912.835606887426.8118079708-28.3686689386
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 1 through 43 )1 - 431 - 43
22chain 'A' and (resid 44 through 91 )44 - 9144 - 91
33chain 'A' and (resid 92 through 110 )92 - 11092 - 110
44chain 'A' and (resid 111 through 214 )111 - 214111 - 214
55chain 'A' and (resid 215 through 292 )215 - 292215 - 292
66chain 'A' and (resid 293 through 306 )293 - 306293 - 306

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