Interaction of the indole class of vacuolar H(+)-ATPase inhibitors with lipid bilayers

Biochemistry
F FernandesM Prieto

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.

Citations

Dec 12, 2007·Journal of Peptide Science : an Official Publication of the European Peptide Society·Renske W HesselinkManuel Prieto
Sep 26, 2006·Biochimica Et Biophysica Acta·F FernandesM A Hemminga
Sep 21, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Renukadevi PatilKenneth D Beaman
Jan 20, 2009·The Journal of Experimental Biology·Markus Huss, Helmut Wieczorek

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