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.
|Number of pages||15|
|Journal||Journal of Biological Chemistry|
|State||Published - Dec 19 2014|
Bibliographical notePublisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. This work was supported in whole or in part by National Institutes of Health Grant NS38041 (to D. W. R.).
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology