Structure of a bacterial multidrug ABC transporter

Area of Science:

• Structural biology
• Molecular biology
• Biochemistry

Background:

• Multidrug transporters, particularly ATP-binding cassette (ABC) transporters, are crucial for exporting cytotoxic drugs across cell membranes.
• Tumour cells can develop resistance to chemotherapy agents through the action of these multidrug transporters.
• Understanding the molecular mechanisms of these transporters is vital for overcoming drug resistance in cancer therapy.

Purpose of the Study:

• To elucidate the molecular basis of multidrug transport by determining the crystal structure of a bacterial ABC transporter.
• To provide a structural model for the drug export mechanism relevant to multidrug resistance.

Main Methods:

• X-ray crystallography was employed to determine the 3.0 Å crystal structure of the Staphylococcus aureus ABC transporter, Sav1866.
• Structural analysis was performed and compared with existing data from related proteins like human MDR1 and bacterial MsbA.

Main Results:

• The crystal structure revealed Sav1866 as a homodimer comprising 12 transmembrane helices.
• The determined structure adopts an outward-facing conformation, indicative of the ATP-bound state.
• The nucleotide-binding domains are in close proximity, and the transmembrane domains form a central cavity, likely representing the drug translocation pathway, open to the extracellular space.

Conclusions:

• The Sav1866 structure provides a molecular blueprint for an outward-facing ABC transporter.
• This conformation suggests a mechanism for shielding the drug translocation pathway from the cytoplasm and inner lipid bilayer.
• The findings offer critical insights into the function of multidrug resistance proteins and potential targets for therapeutic intervention.