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- PDB-9cdl: SARS-CoV-2 Mpro E166V/L50F double mutant in complex with small mo... -

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Basic information

Entry
Database: PDB / ID: 9cdl
TitleSARS-CoV-2 Mpro E166V/L50F double mutant in complex with small molecule inhibitor Mpro61
Components3C-like proteinase nsp5
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Main protease / Mpro / 3CL / drug resistant mutant / E166V / L50F / antiviral / inhibitor / Mpro61
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / ISG15-specific peptidase activity / TRAF3-dependent IRF activation pathway / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / snRNP Assembly / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / SARS coronavirus main proteinase / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / 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 toll-like receptor signaling pathway / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / SARS-CoV-2 modulates host translation machinery / mRNA (guanine-N7)-methyltransferase / host cell Golgi apparatus / methyltransferase cap1 / symbiont-mediated perturbation of host ubiquitin-like protein modification / symbiont-mediated suppression of host NF-kappaB cascade / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / forked DNA-dependent helicase activity / single-stranded 3'-5' DNA helicase activity / four-way junction helicase activity / double-stranded DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / lipid binding / 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 (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : ...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 (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / 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. / 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 / (+) RNA virus helicase core domain / (+)RNA virus helicase core 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 / 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 / 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 3Ecto domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile.
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å
AuthorsTang, S. / Kenneson, J.R. / Huynh, K. / Anderson, K.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1U19AI171443 United States
CitationJournal: Acs Bio Med Chem Au / Year: 2025
Title: Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (M pro ) with Noncovalent Preclinical Candidate, Mpro61.
Authors: Kenneson, J.R. / Papini, C. / Tang, S. / Huynh, K. / Zhang, C.H. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionJun 25, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: 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

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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)34,3952
Polymers33,8301
Non-polymers5651
Water4,612256
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7904
Polymers67,6592
Non-polymers1,1312
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3080 Å2
ΔGint-16 kcal/mol
Surface area24600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.689, 54.545, 44.433
Angle α, β, γ (deg.)90.00, 101.24, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-690-

HOH

21A-694-

HOH

31A-718-

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: 33829.578 Da / Num. of mol.: 1 / Mutation: E166V, L50F
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-XEK / (5P)-5-[(1P,3M,3'P)-3-{3-chloro-5-[(2-chlorophenyl)methoxy]-4-fluorophenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl]-1-methylpyrimidine-2,4(1H,3H)-dione


Mass: 565.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H19Cl2FN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 290 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES pH 6.0-6.5, 10% 2-propanol, 15-20% PEG3350
PH range: 6-6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 14, 2024
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.52→34.07 Å / Num. obs: 41803 / % possible obs: 100 % / Redundancy: 6.8 % / CC1/2: 0.994 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.066 / Rrim(I) all: 0.175 / Χ2: 0.92 / Net I/σ(I): 6.2 / Num. measured all: 284027
Reflection shellResolution: 1.52→1.6 Å / % possible obs: 100 % / Redundancy: 5.6 % / Rmerge(I) obs: 1.688 / Num. measured all: 34063 / Num. unique obs: 6073 / CC1/2: 0.441 / Rpim(I) all: 0.776 / Rrim(I) all: 1.863 / Χ2: 0.81 / Net I/σ(I) obs: 1

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
autoPROCdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.52→31.7 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2107 2071 4.96 %
Rwork0.1846 --
obs0.1858 41740 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.52→31.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2359 0 39 256 2654
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006
X-RAY DIFFRACTIONf_angle_d0.774
X-RAY DIFFRACTIONf_dihedral_angle_d13.516892
X-RAY DIFFRACTIONf_chiral_restr0.05377
X-RAY DIFFRACTIONf_plane_restr0.009446
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.52-1.560.28361230.30462616X-RAY DIFFRACTION98
1.56-1.590.31331560.29542589X-RAY DIFFRACTION100
1.59-1.640.3051600.2832611X-RAY DIFFRACTION100
1.64-1.690.29061260.24862636X-RAY DIFFRACTION100
1.69-1.740.25431300.23172626X-RAY DIFFRACTION100
1.74-1.80.26631200.22352664X-RAY DIFFRACTION100
1.8-1.880.22811400.21022664X-RAY DIFFRACTION100
1.88-1.960.23841100.19812643X-RAY DIFFRACTION100
1.96-2.060.23851510.18672636X-RAY DIFFRACTION100
2.06-2.190.21881420.17912631X-RAY DIFFRACTION100
2.19-2.360.22581350.18152662X-RAY DIFFRACTION100
2.36-2.60.23841330.18992651X-RAY DIFFRACTION100
2.6-2.980.19541540.18792647X-RAY DIFFRACTION100
2.98-3.750.1711490.16552669X-RAY DIFFRACTION100
3.75-31.70.17381420.14862724X-RAY DIFFRACTION100
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)
12.0648-0.62650.75541.7937-0.76131.02920.1753-0.1287-0.358-0.14490.11320.32830.1963-0.1598-0.22430.1521-0.015-0.01430.14750.03480.22157.8435-10.39729.2281
20.4263-1.4308-0.68066.48982.74441.2175-0.1-0.42650.14521.18040.1897-0.0123-0.0191-0.43390.04090.37840.08940.02170.31060.02170.196418.7535-7.071429.1021
31.1741-0.48470.1782.01950.07741.44080.0846-0.2975-0.29250.26090.16830.47910.3781-0.3749-0.13830.2573-0.0429-0.01950.26630.1210.344813.8789-19.728119.4985
42.0048-0.22590.94082.5779-0.9621.55580.0394-0.0338-0.1095-0.20730.05970.17050.1428-0.0777-0.05990.1272-0.0040.0030.11010.00810.108811.2148-4.34156.8242
51.1255-0.3058-0.06381.5507-0.81261.1984-0.14840.12890.14640.2826-0.0234-0.1541-0.38070.07820.12760.1412-0.02040.00690.11670.00050.131315.29979.17624.773
61.7322-0.3253-0.84931.6090.79291.05110.07840.39830.4615-0.15440.0722-0.2171-0.2022-0.033-0.10850.2210.00810.01760.26020.08280.24616.796119.7314-10.0284
73.063-0.405-0.22750.95820.62982.92450.05320.41570.1312-0.0338-0.03090.01440.03-0.3761-0.02980.1816-0.02080.00180.29980.06380.17418.863713.6045-10.3126
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 43 )
2X-RAY DIFFRACTION2chain 'A' and (resid 44 through 59 )
3X-RAY DIFFRACTION3chain 'A' and (resid 60 through 91 )
4X-RAY DIFFRACTION4chain 'A' and (resid 92 through 180 )
5X-RAY DIFFRACTION5chain 'A' and (resid 181 through 213 )
6X-RAY DIFFRACTION6chain 'A' and (resid 214 through 250 )
7X-RAY DIFFRACTION7chain 'A' and (resid 251 through 305 )

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