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PDBsum entry 4m3m

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protein ligands metals links
Hydrolase/hydrolase inhibitor PDB id
4m3m
Jmol
Contents
Protein chain
390 a.a.
Ligands
22N
NAG
Metals
_CA
Waters ×428
PDB id:
4m3m
Name: Hydrolase/hydrolase inhibitor
Title: Influenza neuraminidase in complex with a stereomutated anal oseltamivir carboxylate
Structure: Neuraminidase. Chain: a. Fragment: unp residues 80-469
Source: Influenza a virus. Organism_taxid: 385580. Strain: a/duck/ukraine/1/1963 (h3n8)
Resolution:
2.10Å     R-factor:   0.177     R-free:   0.215
Authors: P.S.Kerry
Key ref: A.Sartori et al. (2014). Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate. Org Biomol Chem, 12, 1561-1569. PubMed id: 24425043 DOI: 10.1039/c3ob42069h
Date:
06-Aug-13     Release date:   12-Feb-14    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q07599  (NRAM_I63A3) -  Neuraminidase
Seq:
Struc:
470 a.a.
390 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 8 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.2.1.18  - Exo-alpha-sialidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)-glycosidic linkages of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   3 terms 
  Biological process     carbohydrate metabolic process   1 term 
  Biochemical function     exo-alpha-sialidase activity     1 term  

 

 
DOI no: 10.1039/c3ob42069h Org Biomol Chem 12:1561-1569 (2014)
PubMed id: 24425043  
 
 
Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate.
A.Sartori, L.Dell'Amico, L.Battistini, C.Curti, S.Rivara, D.Pala, P.S.Kerry, G.Pelosi, G.Casiraghi, G.Rassu, F.Zanardi.
 
  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 (), accessed in 15 steps from glyceraldehyde, o-anisidine and pyrrole siloxydiene precursors. Compound 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.