Structure of neprilysin in complex with the active metabolite of sacubitril

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 comp...

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Detalles Bibliográficos
Autores principales: Schiering, Nikolaus, D’Arcy, Allan, Villard, Frederic, Ramage, Paul, Logel, Claude, Cumin, Frederic, Ksander, Gary M., Wiesmann, Christian, Karki, Rajeshri G., Mogi, Muneto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908401/
https://www.ncbi.nlm.nih.gov/pubmed/27302413
http://dx.doi.org/10.1038/srep27909
Descripción
Sumario: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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