9CMS

Room-temperature X-ray structure of SARS-CoV-2 main protease drug resistant mutant (E166V) in complex with ensitrelvir (ESV)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.159 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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Literature

Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors.

Kovalevsky, A.Aniana, A.Ghirlando, R.Coates, L.Drago, V.N.Wear, L.Gerlits, O.Nashed, N.T.Louis, J.M.

(2024) J Med Chem 67: 18478-18490

  • DOI: https://doi.org/10.1021/acs.jmedchem.4c01781
  • Primary Citation of Related Structures:  
    9CMJ, 9CMN, 9CMS, 9CMU

  • PubMed Abstract: 

    SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), and L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal autoprocessing to produce mature MPro with dimer dissociation constants ( K dimer ) 2-3 times larger than that of the wildtype. Co-selection of L50F restores catalytic activity of DRM2 and DRM4 from ∼10 to 30%, relative to that of the wild-type enzyme, without altering K dimer . Binding affinities and thermodynamic profiles that parallel the drug selection pressure, exhibiting significant decreases in affinity through entropy/enthalpy compensation, were compared with GC373. Reorganization of the active sites due to mutations observed in the inhibitor-free DRM3 and DRM4 structures as compared to MPro WT may account for the reduced binding affinities, although DRM2 and DRM3 complexes with ensitrelvir are almost identical to MPro WT -ensitrelvir. Chemical reactivity changes of the mutant active sites due to differences in electrostatic and protein dynamics effects likely contribute to losses in binding affinities.


  • Organizational Affiliation

    Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3C-like proteinase nsp5
A, B
306Severe acute respiratory syndrome coronavirus 2Mutation(s): 1 
Gene Names: rep1a-1b
EC: 3.4.22.69
UniProt
Find proteins for P0DTD1 (Severe acute respiratory syndrome coronavirus 2)
Explore P0DTD1 
Go to UniProtKB:  P0DTD1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0DTD1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7YY (Subject of Investigation/LOI)
Query on 7YY

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione
C22 H17 Cl F3 N9 O2
QMPBBNUOBOFBFS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.159 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.195α = 90
b = 101.26β = 107.74
c = 59.374γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 7YYClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-10-16
    Type: Initial release
  • Version 1.1: 2024-11-06
    Changes: Database references