Open AccessAn embedded lipid in the multidrug transporter LmrP suggests a mechanism for polyspecificity
Author(s) -
Vincent Debruycker,
Andrew Hutchin,
Matthieu Masureel,
Emel Ficici,
Chloé Martens,
Pierre Legrand,
Richard A. Stein,
Hassane S. Mchaourab,
José Faraldo-Gómez,
Han Remaut,
Cédric Govaerts
Publication year - 2020
Publication title -
nature structural and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.448
H-Index - 270
eISSN - 1545-9993
pISSN - 1545-9985
DOI - 10.1038/s41594-020-0464-y
Subject(s) - major facilitator superfamily , efflux , transporter , atp binding cassette transporter , lactococcus lactis , lipid a , chemistry , ligand (biochemistry) , lipid ii , multiple drug resistance , plasma protein binding , biophysics , mutant , lipid bilayer , biochemistry , binding site , biology , membrane , bacteria , receptor , antibiotics , enzyme , genetics , gene , biosynthesis , lactic acid
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.