Allosteric inhibition of the neuropeptidase neurolysin

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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish
Pages (from-to)35605-35619
Number of pages15
JournalJournal of Biological Chemistry
Issue number51
StatePublished - Dec 19 2014

Bibliographical note

Publisher 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

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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