Protonation drives the conformational switch in the multidrug transporter LmrP
By M. Masureel, Chloé Martens, Richard A. Stein, Smriti Mishra, J. Ruysschaert, Hassane S. Mchaourab, C. Govaerts. 2013
80 citations recorded by the source corpus.
Multidrug antiporters of the Major Facilitator Superfamily couple proton translocation to the extrusion of cytotoxic molecules. The conformational changes that underlie the transport cycle and the structural basis of coupling of these transporters have not been elucidated. Here we utilized extensive Double Electron Electron Resonance measurements to uncover the conformational equilibrium of LmrP, a multidrug transporter from L. lactis, and to investigate how protons and ligands shift this equilibrium to enable transport. We find that the transporter switches between outward-open and outward-closed conformations depending on the protonation states of specific acidic residues forming a transmembrane protonation relay. Our data can be framed in a model of transport wherein substrate binding initiates the transport cycle by opening the extracellular side. Subsequent protonation of membrane-embedded acidic residues induces substrate release to the extracellular side and triggers a cascade of conformational changes that concludes in proton release to the intracellular side.
Subfields: Biophysics, 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 ).”
- AlphaFold2 predicts the inward-facing conformation of the multidrug transporter LmrP (2021, background): “Active transporters such as LmrP alternate between outward- and inward-facing conformations (OF and IF, respectively) during their transport cycles.(1-3) Whereas the crystal structure captures LmrP in the former,(4) AlphaFold2 modeled LmrP in the latter(5) (Figure 1A).”