Active-Site-Directed Inhibitors of Prolyl Oligopeptidase Abolish Its Conformational Dynamics

作者：Lopez Abraham; Herranz Trillo Fatima; Kotev Martin; Gairi Margarida; Guallar Victor; Bernado Pau; Millet Oscar; Tarrago Teresa; Giralt Ernest^*

来源：ChemBioChem, 2016, 17(10): 913-917.

DOI：10.1002/cbic.201600102

• NMR spectroscopy
• prolyl oligopeptidase
• protein dynamics
• protein-protein interactions
• SAXS

Deciphering conformational dynamics is crucial for understanding the biological functions of proteins and for designing compounds targeting them. In particular, providing an accurate description of microsecond-millisecond motions opens the opportunity for regulating protein-protein interactions (PPIs) by modulating the dynamics of one interacting partner. Here we analyzed the conformational dynamics of prolyl oligopeptidase (POP) and the effects of active-site-directed inhibitors on the dynamics. We used an integrated structural biology approach based on NMR spectroscopy and SAXS experiments complemented by MD simulations. We found that POP is in a slow equilibrium in solution between open and closed conformations, and that inhibitors effectively abolished this equilibrium by stabilizing the enzyme in the closed conformation.

• 出版日期2016-5-17