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- PDB-7tia: Crystal structure of SARS-CoV-2 3CL in complex with inhibitor NK01-14 -

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Entry
Database: PDB / ID: 7tia
TitleCrystal structure of SARS-CoV-2 3CL in complex with inhibitor NK01-14
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN/INHIBITOR / VIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


viral genome replication / methyltransferase activity / regulation of autophagy / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / endonuclease activity / 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 ...viral genome replication / methyltransferase activity / regulation of autophagy / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / endonuclease activity / 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 / methylation / 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 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
Coronavirus replicase NSP2, C-terminal / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / Thrombin, subunit H / 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 ...Coronavirus replicase NSP2, C-terminal / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / Thrombin, subunit H / 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 single-stranded poly(A) binding domain / 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 / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / : / Coronavirus replicase NSP2, N-terminal / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / 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 / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / : / : / Coronavirus Nsp3 ectodomain (3Ecto) 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. / Coronavirus main protease (M-pro) 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 replicase NSP9 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
THIOCYANATE ION / Chem-XTP / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 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 support1items
OrganizationGrant numberCountry
Not funded
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 13, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)34,2873
Polymers33,8261
Non-polymers4622
Water3,063170
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5746
Polymers67,6512
Non-polymers9234
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
Buried area3120 Å2
ΔGint-19 kcal/mol
Surface area25480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.551, 81.778, 51.876
Angle α, β, γ (deg.)90.000, 114.610, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-556-

HOH

21A-628-

HOH

31A-662-

HOH

41A-668-

HOH

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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: 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
#2: Chemical ChemComp-XTP / benzyl [(2S)-3-cyclopropyl-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-1-oxopropan-2-yl]carbamate


Mass: 403.472 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H29N3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SCN / THIOCYANATE ION


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


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.78 Å3/Da / Density % sol: 55.77 % / 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: Sep 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.57→47.17 Å / Num. obs: 50967 / % possible obs: 98.1 % / Redundancy: 6.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.055 / Net I/σ(I): 15.5
Reflection shellResolution: 1.57→1.59 Å / Rmerge(I) obs: 1.704 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2319 / CC1/2: 0.565

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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: 1.64→47.17 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 21.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1905 4495 10.07 %
Rwork0.1726 40129 -
obs0.1744 44624 98.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 156.36 Å2 / Biso mean: 46.6874 Å2 / Biso min: 22.55 Å2
Refinement stepCycle: final / Resolution: 1.64→47.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2340 0 32 172 2544
Biso mean--47.03 50.95 -
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 (%)
1.64-1.660.25171450.26091324146997
1.66-1.680.28971520.23971327147998
1.68-1.70.26131420.2281307144998
1.7-1.720.23181400.21511342148297
1.72-1.740.22821680.20161309147798
1.74-1.770.24231580.2091290144898
1.77-1.790.19671630.18481333149698
1.79-1.820.20441410.18581326146798
1.82-1.850.22151510.17771330148198
1.85-1.880.21291530.16941333148698
1.88-1.910.19611380.18121349148798
1.91-1.940.19821490.18561337148698
1.94-1.980.21651430.18211320146399
1.98-2.020.20941400.18171361150199
2.02-2.070.20711410.19541373151499
2.07-2.110.21081500.18681315146599
2.11-2.170.20021710.18231321149299
2.17-2.230.21921570.18681302145999
2.23-2.290.22381510.19091358150999
2.29-2.370.21831550.191346150199
2.37-2.450.20421460.1881370151699
2.45-2.550.24741620.19411333149599
2.55-2.660.20741390.18851325146499
2.66-2.80.24061500.20031338148898
2.8-2.980.21811640.19461325148999
2.98-3.210.19671380.18911381151999
3.21-3.530.20421300.18321366149698
3.53-4.040.15421630.1611348151199
4.05-5.090.14941490.13231351150098
5.1-47.170.15871460.14591389153598
Refinement TLS params.Method: refined / Origin x: -26.0405 Å / Origin y: 12.4936 Å / Origin z: 59.4222 Å
111213212223313233
T0.2035 Å2-0.0179 Å2-0.0129 Å2-0.2387 Å2-0.0165 Å2--0.2666 Å2
L0.7011 °20.5546 °2-0.2295 °2-1.518 °21.2015 °2--3.4639 °2
S0.0636 Å °-0.0748 Å °-0.056 Å °0.0247 Å °-0.052 Å °-0.0667 Å °-0.1379 Å °-0.0899 Å °0.0104 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 303
2X-RAY DIFFRACTION1allA401 - 402
3X-RAY DIFFRACTION1allS1 - 174

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