Interaction of the Indole Class of Vacuolar H+-ATPase Inhibitors with Lipid Bilayers†Click to copy article linkArticle link copied!
Abstract
The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.
†
This work was supported by Contract QLG-CT-2000-01801 of the European Commission (MIVase Consortium) and by FCT (Portugal) under the Program POCTI. M.A.H. and M.P. are members of the COST D22 Action of the European Union. F.F. acknowledges Grant SFRH/BD/14282/2003 from FCT (Portugal).
‡
Instituto Superior Técnico.
§
Universidade de Évora.
‖
Wageningen University.
⊥
University of Leeds.
*
Corresponding author. E-mail: [email protected]. Telephone: (+351) 218413248. Fax: (+351) 218464455.
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