4M3M

Influenza Neuraminidase in complex with a stereomutated analogue of Oseltamivir carboxylate

PDB DOI: https://doi.org/10.2210/pdb4M3M/pdb

Classification: hydrolase/hydrolase inhibitor
Organism(s): Influenza A virus (A/duck/Ukraine/1/1963(H3N8))
Mutation(s): No

Deposited: 2013-08-06 Released: 2014-02-12
Deposition Author(s): Kerry, P.S.

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

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 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

PubMed: 24425043 Search on PubMed
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. andrea.sartori@unipr.it franca.zanardi@unipr.it.

Macromolecule Content

Total Structure Weight: 43.67 kDa
Atom Count: 3,485
Modelled Residue Count: 390
Deposited Residue Count: 390
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Neuraminidase	A	390	Influenza A virus (A/duck/Ukraine/1/1963(H3N8))	Mutation(s): 0
UniProt
Find proteins for Q07599 (Influenza A virus (strain A/Duck/Ukraine/1/1963 H3N8)) Explore Q07599 Go to UniProtKB: Q07599
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q07599
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
22N Query on 22N Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	(3R,4S,5S)-4-(acetylamino)-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid C₁₄ H₂₄ N₂ O₄ NENPYTRHICXVCS-XQQFMLRXSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A]	D [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

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 = 90.832	α = 90
b = 90.832	β = 90
c = 111.987	γ = 90

Software Package:

Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
PHASER	phasing
PHENIX	refinement
PDB_EXTRACT	data extraction
HKL-2000	data collection

Structure Validation

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Ligand Structure Quality Assessment

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