8WM5

multidrug transporter EfpA from Mycobacterium tuberculosis bound with lipids

Summary for 8WM5

• Entry DOI: 10.2210/pdb8wm5/pdb
• EMDB information: 37641
• Descriptor: Efflux pump A, PHOSPHATIDYLETHANOLAMINE, CARDIOLIPIN (3 entities in total)
• Functional Keywords: multidrug transporter, efpa, mycobacterium, lipid, transport protein
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 115640.40

Authors

Wang, S.,Liao, M. (deposition date: 2023-10-03, release date: 2024-09-11, Last modification date: 2024-09-18)

Primary citation

Wang, S.,Wang, K.,Song, K.,Lai, Z.W.,Li, P.,Li, D.,Sun, Y.,Mei, Y.,Xu, C.,Liao, M.
Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition.
Nat Commun, 15:7710-7710, 2024

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 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.

PubMed: 39231991
DOI: 10.1038/s41467-024-51948-9

Experimental method

ELECTRON MICROSCOPY (3.04 Å)