Allosteric Inhibition of the Neuropeptidase Neurolysin |
| |
Authors: | Christina S Hines Kallol Ray Jack J Schmidt Fei Xiong Rolf W Feenstra Mia Pras-Raves Jan Peter de Moes Jos H M Lange Manana Melikishvili Michael G Fried Paul Mortenson Michael Charlton Yogendra Patel Stephen M Courtney Chris G Kruse David W Rodgers |
| |
Institution: | From the ‡Department of Molecular and Cellular Biochemistry and the Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, ;§Abbott Healthcare Products B.V., C.J. van Houtenlaan 36, 1381 CP, Weesp, The Netherlands, and ;¶Evotec (UK) Ltd., 114 Milton Park, Abingdon, OX14 4SA Oxfordshire, United Kingdom |
| |
Abstract: | Neuropeptidases specialize in the hydrolysis of the small bioactive peptides that play a variety of signaling roles in the nervous and endocrine systems. One neuropeptidase, neurolysin, helps control the levels of the dopaminergic circuit modulator neurotensin and is a member of a fold group that includes the antihypertensive target angiotensin converting enzyme. We report the discovery of a potent inhibitor that, unexpectedly, binds away from the enzyme catalytic site. The location of the bound inhibitor suggests it disrupts activity by preventing a hinge-like motion associated with substrate binding and catalysis. In support of this model, the inhibition kinetics are mixed, with both noncompetitive and competitive components, and fluorescence polarization shows directly that the inhibitor reverses a substrate-associated conformational change. This new type of inhibition may have widespread utility in targeting neuropeptidases. |
| |
Keywords: | Allosteric Regulation Hydrolase Metalloprotease Neurochemistry Neuropeptide Peptidase X-ray Crystallography |
|
|