Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition.
Shuhui WangKun WangKangkang SongZon Weng LaiPengfei LiDongying LiYajie SunYe MeiChen XuMaofu LiaoPublished in: Nature communications (2024)
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.
Keyphrases
- mycobacterium tuberculosis
- fatty acid
- mitral valve
- aortic valve
- pulmonary tuberculosis
- minimally invasive
- high resolution
- molecular dynamics simulations
- drug resistant
- signaling pathway
- cancer therapy
- genome wide
- emergency department
- dna methylation
- single cell
- drug induced
- mass spectrometry
- gene expression
- multidrug resistant
- dna binding
- transcription factor
- amino acid
- protein protein