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Structure of neprilysin in complex with the active metabolite of sacubitril

Schiering, Nikolaus and D'Arcy, Allan and Villard, Frederic and Ramage, Paul and Logel, Claude and Cumin, Frederic and Ksander, Gary and Wiesmann, Christian and Karki, Rajeshri and Mogi, Muneto (2016) Structure of neprilysin in complex with the active metabolite of sacubitril. Nature Scientific Reports, 6 (27909 ). pp. 1-5. ISSN 2045-2322

Abstract

Sacubitril is an ethyl ester prodrug of LBQ657, the active neprilysin (NEP) inhibitor, and is a component of LCZ696 (sacubitril/valsartan). We report herein the three-dimensional structure of LBQ657 in complex with human NEP at 2Å resolution. The X-ray structure unravels the binding mode of the compound spanning 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.

Item Type: Article
Date Deposited: 15 Jun 2016 23:45
Last Modified: 15 Jun 2016 23:45
URI: https://oak.novartis.com/id/eprint/28024

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