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Structures of the essential efflux pump EfpA from Mycobacterium tuberculosis reveal the mechanisms of substrate transport and small-molecule inhibition
Open accessPreprint — published as 10.1038/s41467-024-51948-9 · Paper page
Abstract
As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Herein we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites, and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Wang, S., Wang, K., Song, K., Li, P., Li, D., Sun, Y., Mei, Y., Xu, C., & Liao, M.
- Affiliations
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Single Particle, LLC
- Wuhan Union Hospital (CN)
- East China Normal University (CN)
- Southern University of Science and Technology (CN)
- Corresponding author
- Wang, Shuhui
- Liao, Maofu
- Venue
- Nature Communications
- Published
- 2024-01-05
- Volume
- 15
- Issue
- 1
- Pages
- 7710-7710
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11375168
- OpenAlex
- W4402231721
- Cited by
- 18
- References
- 1
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 1
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Energy
- Oregon Health and Science University (436923)
- National Natural Science Foundation of China (32330054)
- Southern University of Science and Technology
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences (U24GM129547)
- Biological and Environmental Research
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- Mycobacterium tuberculosis, multidrug efflux pumps, lipid flippase, lipid binding, outward-open conformation, inward-open conformation, MFSD2A, tuberculosis drug targets, cryo-EM structure
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