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- PDB-7tiz: Crystal structure of SARS-CoV-2 3CL in complex with inhibitor NK01-63 -

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Entry
Database: PDB / ID: 7tiz
TitleCrystal structure of SARS-CoV-2 3CL in complex with inhibitor NK01-63
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN/INHIBITOR / VIRAL 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 / SARS-CoV-2 modulates host translation machinery / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / methylation / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / 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 / 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 / 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 Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus 3Ecto domain profile. / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, 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 / 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-N63 / THIOCYANATE ION / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsForouhar, F. / Liu, H. / Iketani, S. / Zack, A. / Khanizeman, N. / Bednarova, E. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. ...Forouhar, F. / Liu, H. / Iketani, S. / Zack, A. / Khanizeman, N. / Bednarova, E. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. / Huang, Y. / Tay, N.E.S. / Lee, S. / Karan, C. / Resnick, S.J. / Quinn, C. / Li, W. / Shion, H. / Jurtschenko, C. / Lauber, M.A. / McDonald, T. / Stokes, M.E. / Hurst, B. / Rovis, T. / Chavez, A. / Ho, D.D. / Stockwell, B.R.
Funding support7items
OrganizationGrant numberCountry
Jack Ma Foundation
Burroughs Wellcome Fund
Columbia Technology Ventures
Columbia Translational Therapeutics (TRx)
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)T32AI106711
National Science Foundation (NSF, United States)2029943
Department of Energy (DOE, United States)DE-AC02-06CH11357
CitationJournal: Nat Commun / Year: 2022
Title: Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.
Authors: Liu, H. / Iketani, S. / Zask, A. / Khanizeman, N. / Bednarova, E. / Forouhar, F. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. / Huang, Y. / Tay, N.E.S. / Lee, S. / Karan, C. / Resnick, ...Authors: Liu, H. / Iketani, S. / Zask, A. / Khanizeman, N. / Bednarova, E. / Forouhar, F. / Fowler, B. / Hong, S.J. / Mohri, H. / Nair, M.S. / Huang, Y. / Tay, N.E.S. / Lee, S. / Karan, C. / Resnick, S.J. / Quinn, C. / Li, W. / Shion, H. / Xia, X. / Daniels, J.D. / Bartolo-Cruz, M. / Farina, M. / Rajbhandari, P. / Jurtschenko, C. / Lauber, M.A. / McDonald, T. / Stokes, M.E. / Hurst, B.L. / Rovis, T. / Chavez, A. / Ho, D.D. / Stockwell, B.R.
History
DepositionJan 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 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 nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5225
Polymers33,8261
Non-polymers6974
Water4,089227
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,04410
Polymers67,6512
Non-polymers1,3938
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
Buried area3820 Å2
ΔGint-33 kcal/mol
Surface area25380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.433, 81.640, 51.831
Angle α, β, γ (deg.)90.000, 114.500, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-547-

HOH

21A-638-

HOH

31A-642-

HOH

41A-673-

HOH

51A-711-

HOH

61A-721-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 3C-like proteinase nsp5 / 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
Production host: Escherichia coli (E. coli)
References: UniProt: P0DTC1, SARS coronavirus main proteinase

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Non-polymers , 5 types, 231 molecules

#2: Chemical ChemComp-N63 / (1S,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-2-{[N-({[3-(trifluoromethyl)phenyl]methoxy}carbonyl)-L-leucyl]amino}propane-1-sulfonic acid


Mass: 553.549 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H30F3N3O8S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.77 Å3/Da / Density % sol: 55.64 % / Description: block-shaped
Crystal growTemperature: 277 K / Method: microbatch / pH: 5
Details: 0.1 M potassium thiocyanate, 0.1 M sodium acetate, pH 5, and 20% (w/v) PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 7, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.49→47.17 Å / Num. obs: 59352 / % possible obs: 97.8 % / Redundancy: 6.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.056 / Net I/σ(I): 16.7
Reflection shellResolution: 1.49→1.51 Å / Redundancy: 6.1 % / Rmerge(I) obs: 1.682 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2628 / CC1/2: 0.574 / % possible all: 87.7

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JSU

7jsu


Resolution: 1.55→47.17 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1906 5127 9.75 %
Rwork0.1704 47476 -
obs0.1724 52603 98.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 177.74 Å2 / Biso mean: 41.705 Å2 / Biso min: 15.56 Å2
Refinement stepCycle: final / Resolution: 1.55→47.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2340 0 41 228 2609
Biso mean--43.32 49.4 -
Num. residues----303
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.55-1.570.29381590.27921539169896
1.57-1.590.25571840.26041555173997
1.59-1.610.27881700.24691515168597
1.61-1.630.24031820.23041572175497
1.63-1.650.24661440.21921564170897
1.65-1.670.22281750.20431569174497
1.67-1.690.19151780.18331531170998
1.69-1.720.18771680.18491599176798
1.72-1.750.24191740.18821554172898
1.75-1.770.2351440.19891609175398
1.77-1.80.22391630.18191587175098
1.8-1.840.22411730.17521591176498
1.84-1.870.19571670.17171562172998
1.87-1.910.19611700.17861585175599
1.91-1.950.20391720.17731564173699
1.95-20.22651800.18021627180799
2-2.050.18131580.1871585174399
2.05-2.10.19791830.18151543172699
2.1-2.170.2061780.17811604178299
2.17-2.240.20331700.17561592176299
2.24-2.320.18311710.18451556172798
2.32-2.410.20541540.17591604175899
2.41-2.520.20861930.18831586177999
2.52-2.650.2161820.17811599178199
2.65-2.820.21511730.191515931766100
2.82-3.030.21951510.18811659181099
3.03-3.340.18831770.18231578175599
3.34-3.820.16331790.1641598177799
3.82-4.810.15351710.13391615178699
4.81-47.170.17631840.14551641182599
Refinement TLS params.Method: refined / Origin x: -25.9644 Å / Origin y: 12.5181 Å / Origin z: 59.3117 Å
111213212223313233
T0.1607 Å2-0.0291 Å2-0.0045 Å2-0.1779 Å2-0.0122 Å2--0.1945 Å2
L0.6369 °20.0584 °2-0.5057 °2-0.9469 °20.7334 °2--2.9657 °2
S0.0523 Å °-0.0495 Å °-0.0526 Å °-0.0282 Å °-0.0419 Å °-0.0331 Å °-0.1987 Å °-0.0701 Å °0.0222 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 303
2X-RAY DIFFRACTION1allA401 - 404
3X-RAY DIFFRACTION1allS1 - 228

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