ATP occlusion by P-glycoprotein as a surrogate measure for drug coupling |
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| Authors: | Tombline Gregory Holt Jason J Gannon Michael K Donnelly David J Wetzel Bryan Sawada Geri A Raub Thomas J Detty Michael R |
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| Affiliation: | Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, USA. gregory_tombline@urmc.rochester.edu |
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| Abstract: | The multidrug efflux pump P-glycoprotein (Pgp) couples drug transport to ATP hydrolysis. Previously, using a synthetic library of tetramethylrosamine ( TMR) analogues, we observed significant variation in ATPase stimulation ( V m (D)). Concentrations required for half-maximal ATPase stimulation ( K m (D)) correlated with ATP hydrolysis transition-state stabilization and ATP occlusion (EC 50 (D)) at a single site. Herein, we characterize several TMR analogues that elicit modest turnover ( k cat
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