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- PDB-7p2g: Identification of low micromolar SARS-CoV-2 Mpro inhibitors from ... -

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Basic information

Entry
Database: PDB / ID: 7p2g
TitleIdentification of low micromolar SARS-CoV-2 Mpro inhibitors from hits identified by in silico screens
Components3C-like proteinase
KeywordsHYDROLASE / SARS-CoV-2 / Mpro / inhibitor / protease
Function / homology
Function and homology information


SARS coronavirus main proteinase / DNA helicase / ubiquitinyl hydrolase 1 / RNA helicase / RNA-directed RNA polymerase
Similarity search - Function
Viral (Superfamily 1) RNA helicase / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation ...Viral (Superfamily 1) RNA helicase / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / 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 / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / (+) RNA virus helicase core domain / (+)RNA virus helicase core 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 / 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 / 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 / Coronavirus replicase NSP2, N-terminal / Coronavirus replicase NSP2, C-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 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 / Macro domain / Macro domain profile. / Macro domain-like / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-4N0 / 3C-like proteinase
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsRempel, S. / Halazonetis, T.D.
CitationJournal: Sci Rep / Year: 2022
Title: Non-covalent SARS-CoV-2 M pro inhibitors developed from in silico screen hits.
Authors: Rossetti, G.G. / Ossorio, M.A. / Rempel, S. / Kratzel, A. / Dionellis, V.S. / Barriot, S. / Tropia, L. / Gorgulla, C. / Arthanari, H. / Thiel, V. / Mohr, P. / Gamboni, R. / Halazonetis, T.D.
History
DepositionJul 5, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 31, 2024Group: 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

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2182
Polymers33,8261
Non-polymers3921
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.610, 53.790, 45.440
Angle α, β, γ (deg.)90.000, 100.976, 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

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Components

#1: Protein 3C-like proteinase / Growth factor-like peptide / Guanine-N7 methyltransferase / Helicase / Host translation inhibitor ...Growth factor-like peptide / Guanine-N7 methyltransferase / Helicase / Host translation inhibitor nsp1 / Leader protein / NendoU / Non-structural protein 10 / Non-structural protein 2 / Non-structural protein 3 / Non-structural protein 4 / Non-structural protein 6 / Non-structural protein 7 / Non-structural protein 8 / Non-structural protein 9 / ORF1ab polyprotein / Papain-like proteinase / RNA-directed RNA polymerase / Replicase polyprotein 1ab / Uridylate-specific endoribonuclease / p65 homolog


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: ORF1ab / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Gold
References: UniProt: A0A7L9RWV7, RNA-directed RNA polymerase, ubiquitinyl hydrolase 1, SARS coronavirus main proteinase, DNA helicase, RNA helicase
#2: Chemical ChemComp-4N0 / (4~{R})-~{N}-(4-iodophenyl)-2-oxidanylidene-3,4-dihydro-1~{H}-quinoline-4-carboxamide


Mass: 392.191 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13IN2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 2.03 Å3/Da / Density % sol: 39.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1 M Tris, 25% (v/v) PEG 3350, 0.2 M lithium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→48.53 Å / Num. obs: 31270 / % possible obs: 98.65 % / Redundancy: 3.4 % / Biso Wilson estimate: 74.18 Å2 / CC1/2: 0.983 / CC star: 0.996 / Net I/σ(I): 8.38
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.2 % / Num. unique obs: 912 / CC1/2: 0.208 / CC star: 0.587 / % possible all: 97.33

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WQF

6wqf


Resolution: 2.5→48.53 Å / Cross valid method: FREE R-VALUE / σ(F): 1.14 / Phase error: 44.4908
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2774 911 5.05 %
Rwork0.2244 17122 -
obs0.2271 18033 97.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.5→48.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2354 0 21 8 2383
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00182430
X-RAY DIFFRACTIONf_angle_d0.42393304
X-RAY DIFFRACTIONf_chiral_restr0.0386371
X-RAY DIFFRACTIONf_plane_restr0.0034429
X-RAY DIFFRACTIONf_dihedral_angle_d11.1789862
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.630.45241260.43152367X-RAY DIFFRACTION94.4
2.63-2.80.43391280.40782447X-RAY DIFFRACTION98.62
2.8-3.010.41141310.37642522X-RAY DIFFRACTION99.4
3.01-3.320.40271340.31352465X-RAY DIFFRACTION99.5
3.32-3.790.33541310.24622478X-RAY DIFFRACTION98.79
3.8-4.780.19981280.17612419X-RAY DIFFRACTION97.03
4.78-48.530.22261330.1562424X-RAY DIFFRACTION96.67
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)
14.01858667074-0.856898357193.768492872953.45766554679-1.568929800074.633759910930.498360279929-0.666713241929-0.6247862927080.4251389475540.0566269697132-0.07047755318850.535716700074-0.569413373929-0.4684924649040.72756712923-0.133712549919-0.02752162422450.5656629111490.1394327237680.57809821939911.6786230629-14.782043705516.1568251217
23.0100853991-0.5306813152791.445575125424.92923350267-2.769263114096.17854817074-0.2125359469390.1494797353750.2081922252590.199089444551-0.178879715935-0.301994406915-0.02245531689940.2766309075570.3796694939820.569101247851-0.03733932721760.03200577358140.4707869678910.003486069229540.53200813833312.2473999636-0.07229534411736.58351430333
35.90829835607-0.9841773443630.7026615232633.922408739593.173280345468.43478402187-0.1538519845070.4140212336990.584368145689-0.2467841058760.0833119544127-0.413375320919-0.7805109342640.5651354632710.06331160383550.672102071851-0.07463644715480.1037577006240.6138463709750.1554587806040.68746128197712.486675326614.6085580528-8.94273309646
Refinement TLS group

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

IDRefine TLS-IDSelection detailsLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 1 through 100 )A1 - 1001 - 100
22chain 'A' and (resid 101 through 214 )A101 - 214101 - 214
33chain 'A' and (resid 215 through 401 )A - B215 - 401215

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