Structure of neprilysin in complex with the active metabolite of sacubitril

  • Sci Rep. 2016 Jun 15;6:27909. doi: 10.1038/srep27909.
Nikolaus Schiering  1 ,  Allan D'Arcy  1 ,  Frederic Villard  1 ,  Paul Ramage  1 ,  Claude Logel  1 ,  Frederic Cumin  1 ,  Gary M Ksander  2 ,  Christian Wiesmann  1 ,  Rajeshri G Karki  2 ,  Muneto Mogi  2
Affiliations
  • 1. Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
  • 2. Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States.
PMID: 27302413 DOI: 10.1038/srep27909
Abstract

Sacubitril is an ethyl ester prodrug of LBQ657, the active Neprilysin (NEP) inhibitor, and a component of LCZ696 (sacubitril/valsartan). We report herein the three-dimensional structure of LBQ657 in complex with human NEP at 2 Å resolution. The crystal structure unravels the binding mode of the compound occupying the S1, S1' and S2' sub-pockets of the active site, consistent with a competitive inhibition mode. An induced fit conformational change upon binding of the P1'-biphenyl moiety of the inhibitor suggests an explanation for its selectivity against structurally homologous zinc metallopeptidases.

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