Structure of neprilysin in complex with the active metabolite of sacubitril.

Autor: Schiering N; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., D'Arcy A; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., Villard F; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., Ramage P; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., Logel C; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., Cumin F; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., Ksander GM; Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States., Wiesmann C; Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland., Karki RG; Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States., Mogi M; Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2016 Jun 15; Vol. 6, pp. 27909. Date of Electronic Publication: 2016 Jun 15.
DOI: 10.1038/srep27909
Abstrakt: 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.
Databáze: MEDLINE
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