5FDD

Endonuclease inhibitor 1 bound to influenza strain H1N1 polymerase acidic subunit N-terminal region at pH 7.0


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.202 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

Two Distinctive Binding Modes of Endonuclease Inhibitors to the N-Terminal Region of Influenza Virus Polymerase Acidic Subunit

Fudo, S.Yamamoto, N.Nukaga, M.Odagiri, T.Tashiro, M.Hoshino, T.

(2016) Biochemistry 55: 2646-2660

  • DOI: https://doi.org/10.1021/acs.biochem.5b01087
  • Primary Citation of Related Structures:  
    4ZHZ, 4ZI0, 4ZQQ, 5FDD, 5FDG, 5I13

  • PubMed Abstract: 

    Influenza viruses are global threat to humans, and the development of new antiviral agents are still demanded to prepare for pandemics and to overcome the emerging resistance to the current drugs. Influenza polymerase acidic protein N-terminal domain (PAN) has endonuclease activity and is one of the appropriate targets for novel antiviral agents. First, we performed X-ray cocrystal analysis on the complex structures of PAN with two endonuclease inhibitors. The protein crystallization and the inhibitor soaking were done at pH 5.8. The binding modes of the two inhibitors were different from a common binding mode previously reported for the other influenza virus endonuclease inhibitors. We additionally clarified the complex structures of PAN with the same two endonuclease inhibitors at pH 7.0. In one of the crystal structures, an additional inhibitor molecule, which chelated to the two metal ions in the active site, was observed. On the basis of the crystal structures at pH 7.0, we carried out 100 ns molecular dynamics (MD) simulations for both of the complexes. The analysis of simulation results suggested that the binding mode of each inhibitor to PAN was stable in spite of the partial deviation of the simulation structure from the crystal one. Furthermore, crystal structure analysis and MD simulation were performed for PAN in complex with an inhibitor, which was already reported to have a high compound potency for comparison. The findings on the presence of multiple binding sites at around the PAN substrate-binding pocket will provide a hint for enhancing the binding affinity of inhibitors.


  • Organizational Affiliation

    Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Polymerase acidic protein,Polymerase acidic protein191Influenza A virus (A/Puerto Rico/8/1934(H1N1))Mutation(s): 0 
Gene Names: PA
EC: 3.1
UniProt
Find proteins for P03433 (Influenza A virus (strain A/Puerto Rico/8/1934 H1N1))
Explore P03433 
Go to UniProtKB:  P03433
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03433
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
4P8 BindingDB:  5FDD IC50: 6.30e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.202 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.397α = 90
b = 66.397β = 90
c = 127.392γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Japan Society for the Promotion of ScienceJapan24590548

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-30
    Type: Initial release
  • Version 1.1: 2016-05-25
    Changes: Database references
  • Version 1.2: 2020-02-19
    Changes: Data collection, Database references, Derived calculations
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Refinement description