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Molecular basis of multidrug transport by ABC transporters

Markus A Seeger1, Hendrik W van Veen

  • 1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.

Biochimica Et Biophysica Acta
|January 13, 2009
PubMed

Insights

Multidrug ABC transporters like P-glycoprotein (ABCB1) are key to drug resistance. This review explores how ATP hydrolysis in nucleotide-binding domains (NBDs) links to substrate release in membrane domains (MDs).

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Multidrug ABC transporters, including P-glycoprotein (ABCB1), mediate drug efflux, contributing to chemotherapy failure.
  • These transporters comprise nucleotide-binding domains (NBDs) for ATP binding/hydrolysis and membrane domains (MDs) for substrate transport.
  • Overexpression of these transporters is a significant challenge in anticancer and antimicrobial therapies.

Purpose of the Study:

  • To review current evidence on transport models for multidrug ABC transporters.
  • To elucidate the structure-function relationships governing drug binding and release.
  • To reconcile conflicting views on the mechanism linking ATP hydrolysis to substrate transport.

Main Methods:

  • Analysis of recent crystal structures of bacterial ABCB1 homologues (e.g., Sav1866, MsbA).
  • Integration of structural data with existing cellular and biochemical findings.
  • Comparative analysis of different proposed transport models.

Main Results:

  • Recent structural data provide insights into the conformational states of multidrug ABC transporters.
  • Structural information aids in interpreting decades of biochemical and cellular data.
  • Contradictory views exist regarding the coupling of ATP hydrolysis to substrate affinity changes.

Conclusions:

  • Understanding the dynamic interplay between NBDs and MDs is crucial for deciphering transporter function.
  • Structure-function relationships are key to understanding multidrug resistance mechanisms.
  • Further research is needed to fully resolve the catalytic cycle and its link to drug transport.

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