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P-glycoprotein-ATPase modulation: the molecular mechanisms

Li-Blatter, Xiaochun and Beck, Andreas and Seelig, Anna. (2012) P-glycoprotein-ATPase modulation: the molecular mechanisms. Biophysical journal, Vol. 102, H. 6. pp. 1383-1393.

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Official URL: http://edoc.unibas.ch/dok/A6002483

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Abstract

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 rate 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, while 27 closely related ones 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 q=2.7±0.2 (q<3) followed the aforementioned exponential dependence. Small deviations from the optimal ratio strongly reduced the rates ATP hydrolysis and flopping, respectively, while larger deviations lead to the lack of an interaction with the transporter. P-glycoprotein-ATPase inhibition due to membrane disordering by detergents could be fully excluded using 2H-NMR-spectroscopy. Similar principles apply to modulating drugs.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna and Li Blatter, Xiaochun and Beck, Andreas
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Biophysical Society
ISSN:0006-3495
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:11 Oct 2012 15:31
Deposited On:11 Oct 2012 15:20

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