- Meeting abstract
- Open Access
Which conformation does the ABC transporter P-glycoprotein adopt in the physiological membrane environment?
© Stockner et al; licensee BioMed Central Ltd. 2012
- Published: 17 September 2012
- Staphylococcus Aureus
- Multidrug Resistance
- Homology Modeling
- Hydrophobic Region
- Closed Conformation
The human genome contains 48 members of the ABC protein family. We focus on the multidrug resistance transporter P-glycoprotein (P-gp, ABCB1), which is expressed at the blood-brain-barrier, in intestine, kidney, liver and macrophages. The first structure of an ABC exporter was from Staphylococcus aureus and showed a twisted architecture. The same fold was observed in MsbA, mouse P-glycoprotein and the human mitochondrial ABCB10 transporter. Although ABC exporters have now been crystallized in several conformations, uncertainty remained with respect to the physiological conformation because they seem not to be fully compatible with all biochemical evidence.
We applied homology modeling and MD simulations to determine the equilibrium conformation of the membrane-inserted transporter to test the hypothesis whether the observed conformations might be a consequence of the crystallization procedure or conditions. We inserted the transporter model into a pre-equilibrated membrane and carried out equilibrium simulations.
In equilibrium we observe the wings to come close, which is in compliance with experimental observations. Water becomes expelled from the hydrophobic region and the open passage between the water-filled pore and the cell exterior closes. Our results indicate that the closed conformation is energetically more favourable.
The study was funded by the Austrian Science Fund (FWF, grant P23319-B11).
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.