7L8I

SARS-CoV-2 Main Protease (Mpro) in Complex with Rupintrivir (P21)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode.

Lockbaum, G.J.Henes, M.Lee, J.M.Timm, J.Nalivaika, E.A.Thompson, P.R.Kurt Yilmaz, N.Schiffer, C.A.

(2021) Biochemistry 60: 2925-2931

  • DOI: 10.1021/acs.biochem.1c00414
  • Primary Citation of Related Structures:  
    7L8H, 7L8I, 7L8J

  • PubMed Abstract: 
  • Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2 ...

    Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2. In this study, the crystal structures of rupintrivir were determined bound to enterovirus 68 (EV68) 3C protease and the 3C-like main protease (M pro ) from SARS-CoV-2. While the EV68 3C protease-rupintrivir structure was similar to previously determined complexes with other picornavirus 3C proteases, rupintrivir bound in a unique conformation to the active site of SARS-CoV-2 M pro splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.


    Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.



Macromolecules
Find similar proteins by:  (by identity cutoff)  |  Structure
Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
3C-like proteinaseA, B306Severe acute respiratory syndrome coronavirus 2Mutation(s): 0 
Gene Names: rep1a-1b
EC: 3.4.22.69 (PDB Primary Data), 3.4.19.12 (UniProt), 3.4.22 (UniProt), 2.7.7.48 (UniProt), 3.6.4.12 (UniProt), 3.6.4.13 (UniProt), 3.1.13 (UniProt), 3.1 (UniProt), 2.1.1 (UniProt)
UniProt
Find proteins for P0DTD1 (Severe acute respiratory syndrome coronavirus 2)
Explore P0DTD1 
Go to UniProtKB:  P0DTD1
Protein Feature View
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
AG7 (Subject of Investigation/LOI)
Query on AG7

Download Ideal Coordinates CCD File 
C [auth A], D [auth B]4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC ACID ETHYL ESTER
C31 H41 F N4 O7
LMIUALQNZXJHOG-IFILWLFVSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.78α = 90
b = 106.378β = 103.06
c = 54.105γ = 90
Software Package:
Software NamePurpose
HKL-3000data scaling
PHASERphasing
PHENIXrefinement
Cootmodel building
PDB_EXTRACTdata extraction
HKL-3000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment  



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01 GM135919
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR21 AI149716

Revision History  (Full details and data files)

  • Version 1.0: 2021-09-22
    Type: Initial release
  • Version 1.1: 2021-10-13
    Changes: Database references