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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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
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author Schiering, Nikolaus
D’Arcy, Allan
Villard, Frederic
Ramage, Paul
Logel, Claude
Cumin, Frederic
Ksander, Gary M.
Wiesmann, Christian
Karki, Rajeshri G.
Mogi, Muneto
author_facet Schiering, Nikolaus
D’Arcy, Allan
Villard, Frederic
Ramage, Paul
Logel, Claude
Cumin, Frederic
Ksander, Gary M.
Wiesmann, Christian
Karki, Rajeshri G.
Mogi, Muneto
author_sort Schiering, Nikolaus
collection PubMed
description 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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spelling pubmed-49084012016-06-15 Structure of neprilysin in complex with the active metabolite of sacubitril Schiering, Nikolaus D’Arcy, Allan Villard, Frederic Ramage, Paul Logel, Claude Cumin, Frederic Ksander, Gary M. Wiesmann, Christian Karki, Rajeshri G. Mogi, Muneto Sci Rep Article 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. Nature Publishing Group 2016-06-15 /pmc/articles/PMC4908401/ /pubmed/27302413 http://dx.doi.org/10.1038/srep27909 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Schiering, Nikolaus
D’Arcy, Allan
Villard, Frederic
Ramage, Paul
Logel, Claude
Cumin, Frederic
Ksander, Gary M.
Wiesmann, Christian
Karki, Rajeshri G.
Mogi, Muneto
Structure of neprilysin in complex with the active metabolite of sacubitril
title Structure of neprilysin in complex with the active metabolite of sacubitril
title_full Structure of neprilysin in complex with the active metabolite of sacubitril
title_fullStr Structure of neprilysin in complex with the active metabolite of sacubitril
title_full_unstemmed Structure of neprilysin in complex with the active metabolite of sacubitril
title_short Structure of neprilysin in complex with the active metabolite of sacubitril
title_sort structure of neprilysin in complex with the active metabolite of sacubitril
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908401/
https://www.ncbi.nlm.nih.gov/pubmed/27302413
http://dx.doi.org/10.1038/srep27909
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