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1. Biophys J. 2012 Mar 21;102(6):1383-93. Epub 2012 Mar 20.

P-Glycoprotein-ATPase Modulation: The Molecular Mechanisms.

Li-Blatter X, Beck A, Seelig A.

Biophysical Chemistry, Biozentrum, University of Basel, Basel, Switzerland.

P-glycoprotein-ATPase is an efflux transporter of broad specificity that
counteracts passive allocrit influx. Understanding the rate of allocrit transport
therefore matters. Generally, the rates of allocrit transport and ATP hydrolysis
decrease exponentially with increasing allocrit affinity to the transporter. Here
we report unexpectedly strong down-modulation of the P-glycoprotein-ATPase by
certain detergents. To elucidate the underlying mechanism, we chose 34
electrically neutral and cationic detergents with different hydrophobic and
hydrophilic characteristics. Measurement of the P-glycoprotein-ATPase activity as
a function of concentration showed that seven detergents activated the ATPase as
expected, whereas 27 closely related detergents reduced it significantly.
Assessment of the free energy of detergent partitioning into the lipid membrane
and the free energy of detergent binding from the membrane to the transporter
revealed that the ratio, q, of the two free energies of binding determined the
rate of ATP hydrolysis. Neutral (cationic) detergents with a ratio of q = 2.7 ±
0.2 (q > 3) followed the aforementioned exponential dependence. Small deviations
from the optimal ratio strongly reduced the rates of ATP hydrolysis and flopping,
respectively, whereas larger deviations led to an absence of interaction with the
transporter. P-glycoprotein-ATPase inhibition due to membrane disordering by
detergents could be fully excluded using (2)H-NMR-spectroscopy. Similar
principles apply to modulating drugs.

Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights
reserved.

PMCID: PMC3309411 [Available on 2013/3/21]
PMID: 22455921 [PubMed - in process]