Background: Proteins that belong to the ATP-binding cassette superfamily include transporters
that mediate the efflux of substrates from cells. Among these exporters, P-glycoprotein and MRP1
are involved in cancer multidrug resistance, protection from endo and xenobiotics, determination of drug
pharmacokinetics, and the pathophysiology of a variety of disorders.
Objective: To review the information available on ATP-binding cassette exporters, with a focus on Pglycoprotein,
MRP1 and related proteins. We describe tissue localization and function of these transporters
in health and disease, and discuss the mechanisms of substrate transport. We also correlate recent
structural information with the function of the exporters, and discuss details of their molecular mechanism
with a focus on the nucleotide-binding domains.
Methods: Evaluation of selected publications on the structure and function of ATP-binding cassette proteins.
Conclusions: Conformational changes on the nucleotide-binding domains side of the exporters switch
the accessibility of the substrate-binding pocket between the inside and outside, which is coupled to substrate
efflux. However, there is no agreement on the magnitude and nature of the changes at the nucleotide-
binding domains side that drive the alternate-accessibility. Comparison of the structures of Pglycoprotein
and MRP1 helps explain differences in substrate selectivity and the bases for polyspecificity.
P-glycoprotein substrates are hydrophobic and/or weak bases, and polyspecificity is explained by a
flexible hydrophobic multi-binding site that has a few acidic patches. MRP1 substrates are mostly organic
acids, and its polyspecificity is due to a single bipartite binding site that is flexible and displays