New structure model for the ATP-binding cassette multidrug transporter LmrA

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Multidrug resistance in pathogens and tumors is linked to multidrug transporters.
• ATP binding cassette (ABC) transporters utilize ATP hydrolysis for substrate efflux.
• Previous homology models of ABC transporters relied on potentially inaccurate MsbA structures.

Purpose of the Study:

• To remodel the Lactococcus lactis multidrug transporter LmrA using a more accurate structural template.
• To investigate the physiological relevance of the Sav1866 structure for LmrA modeling.
• To elucidate the structural basis for the role of residue E314 in LmrA-mediated transport.

Main Methods:

• Homology modeling of LmrA using Sav1866 crystal coordinates.
• Cysteine cross-linking experiments at three key positions in LmrA.
• Analysis of cross-linking patterns to validate model topology.

Main Results:

• The Sav1866-based LmrA model showed consistency with experimental cysteine cross-linking data.
• This suggests the crystal structure of Sav1866 is physiologically relevant for LmrA.
• Residue E314 is located at the homodimer interface in the inner leaflet, providing a structural basis for its role in proton conduction.

Conclusions:

• The Sav1866 structure provides a more accurate template for modeling LmrA.
• The study offers new structural insights into LmrA-mediated transport and proton conduction.
• This research contributes to understanding multidrug resistance mechanisms.