Schiering, Nikolaus, D'Arcy, Allan, Villard, Frederic, Ramage, Paul, Logel, Claude, Cumin, Frederic, Ksander, Gary, Wiesmann, Christian, 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