Cited by 70Drug Transport and Resistance MechanismsAntibiotic Resistance in BacteriaEnzyme Structure and Function

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

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Debruycker, Vincent, Hutchin, Andrew, Masureel, Matthieu, Ficici, Emel, Martens, Chloé, Legrand, Pierre, Stein, Richard A., Mchaourab, Hassane S. +3 more·2020·Nature Structural & Molecular Biology

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.

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  • AF2 modeled the multidrug transporter LmrP (CASP14 target T1024) in multiple conformations, two of which were individually consistent with published experimental data.

    “Upon examining the list of CASP14 targets and corresponding models, we found that AF2 modeled the multidrug transporter LmrP (target T1024) in multiple conformations, two of which were individually consistent with published experimental data”

    From Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022) · cites this paper as Debruycker et al., 2020

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  1. [24]Winn MD Overview of the CCP4 suite and current developments. Acta Crystallogr. Sect. D Biol. Crystallogr 67, 235– 242 (2011). 21460441 PMC3069738
  2. [39]Kabsch W Xds. Acta Crystallogr. Sect. D Struct. Biol 66, 125– 132 (2010). PMC2815665 20124692
  3. [44]Tickle IJ STARANISO Cambridge, United Kingdom: Global Phasing Ltd. http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi (2018).
  4. [46]Bricogne G BUSTER version 2.10.3 Cambridge, United Kingdom: Global Phasing Ltd. (2016).
  5. [55]Zhang L & Hermans J Hydrophilicity of cavities in proteins. Proteins Struct. Funct. Genet 24, 433– 438 (1996). 9162944

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Authors
Debruycker, V., Hutchin, A., Masureel, M., Ficici, E., Martens, C., Legrand, P., Stein, R. A., Mchaourab, H. S., Faraldo-Gómez, J. D., Remaut, H., & Govaerts, C.
Affiliations
  • Université Libre de Bruxelles (BE)
  • National Institutes of Health (US)
  • Synchrotron SOLEIL (FR)
  • Vanderbilt University Medical Center (US)
  • Vrije Universiteit Brussel (BE)
Corresponding author
Govaerts, Cédric
Venue
Nature Structural & Molecular Biology
Published
2020-07-27
Volume
27
Issue
9
Pages
829-835
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W3044291258
Cited by
69
References
67
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 20 · 2021: 20 · 2020: 3
FWCI
4.70
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Fonds De La Recherche Scientifique - FNRS (F.4523.12)
  • National Institutes of Health
  • Biotechnology and Biological Sciences Research Council (BB/M012573/1)
  • Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
  • National Heart, Lung, and Blood Institute
  • National Institute of General Medical Sciences (R01GM077659)
  • NHLBI Division of Intramural Research
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
multidrug efflux pumps, major facilitator superfamily, substrate-binding cavity, polyspecificity, antibiotic transport, Lactococcus lactis, crystal structure, molecular dynamics simulation, site-directed mutagenesis
MeSH terms
Anti-Bacterial Agents, Bacterial Proteins, Binding Sites, Biological Transport, Ligands, Phosphatidylglycerols, Protein Conformation, Lactococcus lactis, Substrate Specificity, Crystallography, X-Ray, Membrane Transport Proteins, Molecular Dynamics Simulation

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