An embedded lipid in the multidrug transporter LmrP suggests a mechanism for polyspecificity
By V. Debruycker, A. Hutchin, M. Masureel, Emel Ficici, Chloé Martens, Pierre Legrand, Richard A. Stein, Hassane S. Mchaourab, J. Faraldo-Gómez, H. Remaut and 1 more. 2020
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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. A crystal structure of bacterial multidrug transporter LmrP reveals the presence of a lipid inside the substrate binding cavity, with MD simulations and mutational analyses suggesting it could be involved in broad substrate specificity.
Subfields: Genetics, Molecular Medicine, Oncology
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Citations in the corpus
- Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, positive): “…we found that AF2 modeled the multidrug transporter LmrP (target T1024) in multiple conformations, two of which were individually consistent with published experimental data ( Jumper et al., 2021b ; Del Alamo et al., 2021a ; Debruycker et al., 2020 ; Martens et al., 2016 ; Masureel et al., 2014 ).”