8T5W

Influenza PAN endonuclease I38T mutant with Baloxavir


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 

Starting Model: experimental
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Literature

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.

Kohlbrand, A.J.Stokes, R.W.Sankaran, B.Cohen, S.M.

(2024) Biochemistry 63: 264-272

  • DOI: https://doi.org/10.1021/acs.biochem.3c00536
  • Primary Citation of Related Structures:  
    8T5V, 8T5W, 8T5Z, 8T67, 8T6Z, 8T81, 8T94, 8VGZ

  • PubMed Abstract: 

    Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PA N ) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PA N . To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PA N using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PA N . Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.


  • Organizational Affiliation

    Department of Chemistry and Biochemistry, University of California, La Jolla, California 92093, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Polymerase acidic protein192Influenza A virus (A/California/04/2009(H1N1))Mutation(s): 1 
Gene Names: PA
EC: 3.1
UniProt
Find proteins for C3W5S0 (Influenza A virus (strain swl A/California/04/2009 H1N1))
Explore C3W5S0 
Go to UniProtKB:  C3W5S0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupC3W5S0
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.111α = 90
b = 75.111β = 90
c = 121.444γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2024-06-12
    Type: Initial release