4M3M

Influenza Neuraminidase in complex with a stereomutated analogue of Oseltamivir carboxylate

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 

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This is version 1.4 of the entry. See complete history. 


Literature

Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate.

Sartori, A., Dell'amico, L., Battistini, L., Curti, C., Rivara, S., Pala, D., Kerry, P.S., Pelosi, G., Casiraghi, G., Rassu, G., Zanardi, F.

(2014) Org Biomol Chem 12: 1561-1569

  • DOI: https://doi.org/10.1039/c3ob42069h
  • Primary Citation of Related Structures:  
    4M3M

  • PubMed Abstract: 

    A stereodivergent plan is presented leading to all eight stereoisomers of oseltamivir carboxylate (OC). Key chemical manoeuvers are (1) a three-component vinylogous Mukaiyama-Mannich reaction, which sets the whole carbon skeleton and heteroatom substituents, and (2) an intramolecular, silylative Mukaiyama aldol reaction, which creates the targeted carbocycle. The viability of the plan was demonstrated by the first total synthesis of 4-epi-oseltamivir carboxylate (6), accessed in 15 steps from glyceraldehyde, o-anisidine and pyrrole siloxydiene precursors. Compound 6 inhibits influenza A virus strains H1N1 and H3N2 at the μM level, about 150 000-fold less than the OC reference, testifying that the stereodisposition of the C4 acetamido function is key for enzyme recognition. Guided by in-depth structural evaluation including NMR solution studies, molecular mechanics simulations, docking analyses and X-ray crystallography, rationalization of the biological verdict was established.

    • Organizational Affiliation: 

    Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27A, I-43124 Parma, Italy. [email protected] [email protected].


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Neuraminidase390Influenza A virus (A/duck/Ukraine/1/1963(H3N8))Mutation(s): 0 
EC: 3.2.1.18
UniProt
Find proteins for Q07599 (Influenza A virus (strain A/Duck/Ukraine/1/1963 H3N8))
Explore Q07599 
Go to UniProtKB:  Q07599
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07599
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 
  • Space Group: I 4
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.832α = 90
b = 90.832β = 90
c = 111.987γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection

Structure Validation

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Entry History 

Deposition Data

  • Released Date: 2014-02-12 
    • Deposition Author(s): Kerry, P.S.

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-12
    Type: Initial release
  • Version 1.1: 2014-03-26
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.4: 2024-11-20
    Changes: Data collection, Database references, Structure summary