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An embedded lipid in the multidrug transporter LmrP suggests a mechanism for polyspecificity

DOI: 10.1038/s41594-020-0464-y DOI Help

Authors: Vincent Debruycker (Université Libre de Bruxelles) , Andrew Hutchin (Université Libre de Bruxelles) , Matthieu Masureel (Université Libre de Bruxelles) , Emel Ficici (National Heart, Lung and Blood Institute, National Institutes of Health) , Chloé Martens (Université Libre de Bruxelles) , Pierre Legrand (Synchrotron SOLEIL) , Richard A. Stein (Vanderbilt University) , Hassane S. Mchaourab (Vanderbilt University Medical Center) , José D. Faraldo-Gómez (National Heart, Lung and Blood Institute, National Institutes of Health) , Han Remaut (Vrije Universiteit Brussel; VIB-VUB Center for Structural Biology) , Cedric Govaerts (Université Libre de Bruxelles)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 10

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 12718

Abstract: Multidrug efflux pumps present a challenge to the treatment of bacterial infections, making it vitally important to understand their mechanism of action. Here, we investigate the nature of substrate binding within Lactococcus lactis LmrP, a prototypical multidrug transporter of the major facilitator superfamily. We determined the crystal structure of LmrP in a ligand-bound outward-open state and observed an embedded lipid in the binding cavity of LmrP, an observation supported by native mass spectrometry analyses. Molecular dynamics simulations suggest that the anionic lipid stabilizes the observed ligand-bound structure. Mutants engineered to disrupt binding of the embedded lipid display reduced transport of some, but not all, antibiotic substrates. Our results suggest that a lipid within the binding cavity could provide a malleable hydrophobic component that allows adaptation to the presence of different substrates, helping to explain the broad specificity of this protein and possibly other multidrug transporters.

Journal Keywords: Mass spectrometry; Membrane proteins; X-ray crystallography

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 29/07/2020 08:41

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)