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-Structure paper
Title | Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 7710, Year 2024 |
Publish date | Sep 4, 2024 |
Authors | Shuhui Wang / Kun Wang / Kangkang Song / Zon Weng Lai / Pengfei Li / Dongying Li / Yajie Sun / Ye Mei / Chen Xu / Maofu Liao / |
PubMed 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 ...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. Here 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. |
External links | Nat Commun / PubMed:39231991 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.04 - 3.68 Å |
Structure data | EMDB-37641, PDB-8wm5: EMDB-42204, PDB-8ufd: EMDB-42205, PDB-8ufe: |
Chemicals | ChemComp-PTY:
ChemComp-WJI: ChemComp-CDL: |
Source |
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Keywords | TRANSPORT PROTEIN / multidrug efflux pump / EfpA / mycobacterium / BRD8000.3 / Mycobacterium smegmatis / multidrug transporter / lipid |