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The occluded nucleotide conformation of p-glycoprotein
Gregory Tombline1, Alan E Senior
1Department of Biochemistry and Biophysics, University of Rochester Medical Center, Box 712, Rochester, New York 14642, USA.
Journal of Bioenergetics and Biomembranes
|May 13, 2006
Summary
This study reviews the E552A/E1197A P-glycoprotein mutant, revealing it tightly occludes MgATP. This occluded conformation is a transient, asymmetric catalytic intermediate, informing models of P-glycoprotein function.
Area of Science:
- Biochemistry
- Molecular Biology
- Membrane Transport
Background:
- P-glycoprotein is an ATP-binding cassette transporter involved in multidrug resistance.
- Understanding its catalytic mechanism is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To review recent findings on the ATPase-defective E552A/E1197A P-glycoprotein mutant.
- To present a model for P-glycoprotein catalysis incorporating nucleotide binding domain (NBD) dimerization and occluded nucleotide conformation.
Main Methods:
- Biochemical characterization of the E552A/E1197A P-glycoprotein mutant.
- Analysis of MgATP occlusion and stoichiometry.
- Conformational analysis of the occluded nucleotide state.
Main Results:
- The E552A/E1197A mutant occludes MgATP with a 1/1 stoichiometry in a drug-sensitive manner.
- The occluded nucleotide conformation represents a transient, asymmetric catalytic intermediate.
- A model for catalysis is proposed involving NBD dimerization and the occluded conformation.
Conclusions:
- The occluded nucleotide conformation is a key intermediate in P-glycoprotein catalysis.
- The proposed model reconciles asymmetric catalysis with symmetrical NBD dimer structures.
- Further research is needed to fully elucidate the dynamic interplay of NBDs during transport.
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