8HVY

Crystal structure of SARS-Cov-2 main protease K90R mutant in complex with PF07304814


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

Starting Model: experimental
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Literature

Crystal structures of main protease (M pro ) mutants of SARS-CoV-2 variants bound to PF-07304814.

Jiang, H.Zou, X.Zeng, P.Zeng, X.Zhou, X.Wang, J.Zhang, J.Li, J.

(2023) Mol Biomed 4: 23-23

  • DOI: https://doi.org/10.1186/s43556-023-00134-2
  • Primary Citation of Related Structures:  
    8HVU, 8HVV, 8HVW, 8HVX, 8HVY, 8HVZ

  • PubMed Abstract: 

    There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (M pro ) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 M pro with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 M pro . However, the binding modes of PF-07304814 with M pro s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six M pro mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to M pro mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant M pro s. Patterns for PF-07304814 to bind with these investigated M pro mutants and the wild-type M pro are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of M pro mutants when bound to an inhibitor.


  • Organizational Affiliation

    School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3C-like proteinase nsp5
A, B
299Severe acute respiratory syndrome coronavirus 2Mutation(s): 1 
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
80I (Subject of Investigation/LOI)
Query on 80I

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
[(3~{S})-3-[[(2~{S})-2-[(4-methoxy-1~{H}-indol-2-yl)carbonylamino]-4-methyl-pentanoyl]amino]-2-oxidanylidene-4-[(3~{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]butyl] dihydrogen phosphate
C24 H33 N4 O9 P
FQKALOFOWPDTED-WBAXXEDZSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.687α = 90
b = 98.559β = 107.496
c = 58.858γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-01-17
    Type: Initial release
  • Version 1.1: 2024-02-07
    Changes: Database references