4FXY

Crystal structure of rat neurolysin with bound pyrazolidin inhibitor

Summary for 4FXY

• Entry DOI: 10.2210/pdb4fxy/pdb
• Related: 1I1I 2O3E
• Descriptor: Neurolysin, mitochondrial, 1-{(2S)-1-[(3R)-3-(2-chlorophenyl)-2-(2-fluorophenyl)pyrazolidin-1-yl]-1-oxopropan-2-yl}-3-[(1R,3S,5R,7R)-tricyclo[3.3.1.1~3,7~]dec-2-yl]urea, ZINC ION, ... (4 entities in total)
• Functional Keywords: hydrolase, endopeptidase, zinc metallopeptidase, neuropeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rattus norvegicus (rat)
• Total number of polymer chains: 2
• Total formula weight: 159936.23

Authors

Rodgers, D.W.,Hines, C.S. (deposition date: 2012-07-03, release date: 2013-11-13, Last modification date: 2023-09-13)

Primary citation

Hines, C.S.,Ray, K.,Schmidt, J.J.,Xiong, F.,Feenstra, R.W.,Pras-Raves, M.,de Moes, J.P.,Lange, J.H.,Melikishvili, M.,Fried, M.G.,Mortenson, P.,Charlton, M.,Patel, Y.,Courtney, S.M.,Kruse, C.G.,Rodgers, D.W.
Allosteric inhibition of the neuropeptidase neurolysin.
J.Biol.Chem., 289:35605-35619, 2014

PubMed 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.

PubMed: 25378390
DOI: 10.1074/jbc.M114.620930

Experimental method

X-RAY DIFFRACTION (2.8 Å)