6FS9

Influenza B/Memphis/13/03 endonuclease with I38T mutation with bound inhibitor, baloxavir acid (BXA)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.

Omoto, S.Speranzini, V.Hashimoto, T.Noshi, T.Yamaguchi, H.Kawai, M.Kawaguchi, K.Uehara, T.Shishido, T.Naito, A.Cusack, S.

(2018) Sci Rep 8: 9633-9633

  • DOI: https://doi.org/10.1038/s41598-018-27890-4
  • Primary Citation of Related Structures:  
    6FS6, 6FS7, 6FS8, 6FS9, 6FSB

  • PubMed Abstract: 

    Baloxavir acid (BXA), derived from the prodrug baloxavir marboxil (BXM), potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In clinical trials, single doses of BXM profoundly decrease viral titers as well as alleviating influenza symptoms. Here, we characterize the impact on BXA susceptibility and replicative capacity of variant viruses detected in the post-treatment monitoring of the clinical studies. We find that the PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC 50 changes in A and B viruses, respectively. The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro. Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor. A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease. These mechanistic insights provide markers for future surveillance of treated populations.


  • Organizational Affiliation

    Shionogi & Co., Ltd., Osaka, Japan. [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Polymerase acidic protein205Influenza B virus (B/Memphis/13/2003)Mutation(s): 1 
Gene Names: PA
EC: 3.1
UniProt
Find proteins for Q5V8Z9 (Influenza B virus)
Explore Q5V8Z9 
Go to UniProtKB:  Q5V8Z9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ5V8Z9
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 
  • Space Group: I 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.71α = 90
b = 63.71β = 90
c = 125.41γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-11
    Type: Initial release
  • Version 1.1: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description