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 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.
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Nikolaus
N
Schiering
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Allan
A
D'Arcy
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Frederic
F
Villard
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Paul
P
Ramage
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Claude
C
Logel
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Frederic
F
Cumin
Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States.
Gary M
GM
Ksander
Novartis Institutes for BioMedical Research Inc., Fabrikstrasse 16, CH-4002 Basel, Switzerland.
Christian
C
Wiesmann
Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States.
Rajeshri G
RG
Karki
Novartis Institutes for BioMedical Research Inc., 100 Technology Square, Cambridge, Massachusetts, 02139, United States.
Muneto
M
Mogi
D000613:Aminobutyrates / Q000737:chemistry* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D000072417:Protein Domains; D013777:Tetrazoles / Q000378:metabolism; D000068756:Valsartan
D000613:Aminobutyrates; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C000609743:LBQ657; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination