TY - JOUR
T1 - Allosteric inhibition of the neuropeptidase neurolysin
AU - Hines, Christina S.
AU - Ray, Kallol
AU - Schmidt, Jack J.
AU - Xiong, Fei
AU - Feenstra, Rolf W.
AU - Pras-raves, Mia
AU - De Moes, Jan Peter
AU - Lange, Jos H.M.
AU - Melikishvili, Manana
AU - Fried, Michael G.
AU - Mortenson, Paul
AU - Charlton, Michael
AU - Patel, Yogendra
AU - Courtney, Stephen M.
AU - Kruse, Chris G.
AU - Rodgers, David W.
N1 - 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.).
PY - 2014/12/19
Y1 - 2014/12/19
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M114.620930
DO - 10.1074/jbc.M114.620930
M3 - Article
C2 - 25378390
AN - SCOPUS:84919360730
SN - 0021-9258
VL - 289
SP - 35605
EP - 35619
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 51
ER -