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- PDB-7rbz: X-ray Structure of SARS-CoV-2 main protease covalently modified b... -

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Entry
Database: PDB / ID: 7rbz
TitleX-ray Structure of SARS-CoV-2 main protease covalently modified by compound GRL-017-20
Components3C-like proteinase
KeywordsVIRAL PROTEIN / SARS-CoV-2 / COVID-19 / 3CLpro / mpro / 3CL / main / protease / inhibitor / covalent / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID
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 / TRAF3-dependent IRF activation pathway / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / symbiont-mediated suppression of host NF-kappaB cascade / host cell endosome / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA (guanine-N7)-methyltransferase / omega peptidase activity / methyltransferase cap1 / 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 / DNA helicase / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / 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 / lyase activity / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / viral translational frameshifting / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / lipid binding / DNA-templated transcription / 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 / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / : / : / : / Coronavirus Nonstructural protein 13, 1B domain ...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 Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 Interface domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) 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 / Nidovirus 2-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus 3'-5' exoribonuclease domain / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / 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 / 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 / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / 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.
Similarity search - Domain/homology
Chem-4IJ / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsMesecar, A.D. / Anson, B.A. / Ghosh, A.K. / Center for Structural Genomics of Infectious Diseases (CSGID)
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201700060C United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure-Activity Relationship, and X-ray Structural Studies.
Authors: Ghosh, A.K. / Raghavaiah, J. / Shahabi, D. / Yadav, M. / Anson, B.J. / Lendy, E.K. / Hattori, S.I. / Higashi-Kuwata, N. / Mitsuya, H. / Mesecar, A.D.
History
DepositionJul 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1002
Polymers33,8261
Non-polymers2751
Water4,828268
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,2004
Polymers67,6512
Non-polymers5492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3110 Å2
ΔGint-14 kcal/mol
Surface area25510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.495, 82.137, 54.384
Angle α, β, γ (deg.)90.000, 116.908, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-672-

HOH

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Components

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


Mass: 33825.547 Da / Num. of mol.: 1
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)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical ChemComp-4IJ / 5-chloropyridin-3-yl 2,3-dihydro-1H-indole-4-carboxylate


Mass: 274.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11ClN2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer detailsThe inhibitor GRL-017-20 reacts with Cys145 to form a covalent intermediate with a thioester bond. ...The inhibitor GRL-017-20 reacts with Cys145 to form a covalent intermediate with a thioester bond. The chloropyridyl group on the inhibitor leaves after the reaction.

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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: 2.84 Å3/Da / Density % sol: 56.7 %
Crystal growTemperature: 278 K / Method: vapor diffusion / pH: 7.5
Details: 2.67 mM DTT, 0.33% MPD, 16.7 mM MES pH 6.0, 26.7 mM KCl, 5% PEG-10,000, 16.7 mM HEPES pH 7.5, 0.67% DMSO and 200 uM inhibitor

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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 MX300-HS / Detector: CCD / Date: Jul 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.649→29.71 Å / Num. obs: 45449 / % possible obs: 99.79 % / Redundancy: 4.8 % / Biso Wilson estimate: 20.98 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.07787 / Rpim(I) all: 0.03933 / Rrim(I) all: 0.08759 / Net I/σ(I): 16.18
Reflection shellResolution: 1.649→1.798 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.5886 / Mean I/σ(I) obs: 2.42 / Num. unique obs: 4502 / CC1/2: 0.86 / CC star: 0.962 / Rpim(I) all: 0.2891 / Rrim(I) all: 0.6578 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC1.13_2998refinement
PHENIX1.13_2998refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WNP

6wnp


Resolution: 1.65→29.71 Å / SU ML: 0.1766 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.1869 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.1892 2000 4.4 %
Rwork0.1672 43441 -
obs0.1681 45441 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.17 Å2
Refinement stepCycle: LAST / Resolution: 1.65→29.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2358 0 11 268 2637
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112459
X-RAY DIFFRACTIONf_angle_d1.11873347
X-RAY DIFFRACTIONf_chiral_restr0.065375
X-RAY DIFFRACTIONf_plane_restr0.008436
X-RAY DIFFRACTIONf_dihedral_angle_d16.02991448
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.690.28141410.2343061X-RAY DIFFRACTION99.19
1.69-1.740.25621420.21663103X-RAY DIFFRACTION99.94
1.74-1.790.23311440.20733095X-RAY DIFFRACTION100
1.79-1.850.21291410.18083083X-RAY DIFFRACTION100
1.85-1.910.20381420.18123086X-RAY DIFFRACTION99.97
1.91-1.990.21821440.17153118X-RAY DIFFRACTION99.94
1.99-2.080.17281420.16853073X-RAY DIFFRACTION100
2.08-2.190.19531450.16253154X-RAY DIFFRACTION100
2.19-2.320.18211400.15833058X-RAY DIFFRACTION100
2.32-2.50.16651450.16253125X-RAY DIFFRACTION100
2.5-2.760.18721430.17293116X-RAY DIFFRACTION100
2.76-3.150.2151430.16973112X-RAY DIFFRACTION99.94
3.15-3.970.18441440.15753136X-RAY DIFFRACTION99.94
3.97-27.080.16261440.15663121X-RAY DIFFRACTION98.49
Refinement TLS params.Method: refined / Origin x: -5.6897260075 Å / Origin y: 26.1350586266 Å / Origin z: 11.9783755282 Å
111213212223313233
T0.0925330355343 Å2-0.00768251481 Å20.0139038863518 Å2-0.157783512707 Å2-0.00984877364374 Å2--0.134150935128 Å2
L0.960314128648 °20.366123448781 °2-0.0240753636168 °2-2.0384745541 °20.936894864775 °2--2.67198459958 °2
S0.0273324924863 Å °-0.0607795425577 Å °-0.0157362747306 Å °-0.000760638178904 Å °0.0176602208395 Å °-0.104341251701 Å °-0.0147177349333 Å °-0.0882305139755 Å °-0.049437446244 Å °
Refinement TLS groupSelection details: all

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