4CB5

Structure of Influenza A H5N1 PB2 cap-binding domain with bound cap analogue (compound 8f)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.127 
  • R-Value Observed: 0.128 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

New 7-Methyl-Guanosine Derivatives Targeting the Influenza Polymerase Pb2 CAP-Binding Domain

Pautus, S.Sehr, P.Lewis, J.Fortune, A.Wolkerstorfer, A.Szolar, O.Gulligay, D.Lunardi, T.Decout, J.L.Cusack, S.

(2013) J Med Chem 56: 8915

  • DOI: https://doi.org/10.1021/jm401369y
  • Primary Citation of Related Structures:  
    4CB4, 4CB5, 4CB6, 4CB7

  • PubMed Abstract: 

    The heterotrimeric influenza virus polymerase performs replication and transcription of viral RNA in the nucleus of infected cells. Transcription by "cap-snatching" requires that host-cell pre-mRNAs are bound via their 5' cap to the PB2 subunit. Thus, the PB2 cap-binding site is potentially a good target for new antiviral drugs that will directly inhibit viral replication. Docking studies using the structure of the PB2 cap-binding domain suggested that 7-alkylguanine derivatives substituted at position N-9 and N-2 could be good candidates. Four series of 7,9-di- and 2,7,9-trialkyl guanine derivatives were synthesized and evaluated by an AlphaScreen assay in competition with a biotinylated cap analogue. Three synthesized compounds display potent in vitro activity with IC50 values lower than 10 μM. High-resolution X-ray structures of three inhibitors in complex with the H5N1 PB2 cap-binding domain confirmed the binding mode and provide detailed information for further compound optimization.


  • Organizational Affiliation

    Département de Pharmacochimie Moléculaire, Université de Grenoble Alpes/CNRS, UMR 5063 , ICMG FR 2607, 470 rue de la Chimie, BP 53, F-38041 Grenoble, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
POLYMERASE BASIC SUBUNIT 2167Influenza A virus (A/duck/Shantou/4610/2003(H5N1))Mutation(s): 0 
UniProt
Find proteins for Q2LG68 (Influenza A virus)
Explore Q2LG68 
Go to UniProtKB:  Q2LG68
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ2LG68
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.127 
  • R-Value Observed: 0.128 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.17α = 90
b = 82.17β = 90
c = 54.84γ = 120
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: 2013-10-30
    Type: Initial release
  • Version 1.1: 2013-12-25
    Changes: Database references
  • Version 1.2: 2018-04-11
    Changes: Data collection, Source and taxonomy
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description