9BL7

Mycobacterium tuberculosis efpA parallel dimer

This is a non-PDB format compatible entry.

Summary for 9BL7

• Entry DOI: 10.2210/pdb9bl7/pdb
• EMDB information: 44651
• Descriptor: Uncharacterized MFS-type transporter EfpA, (2S)-3-{[(R)-[(2R)-2,3-dihydroxypropoxy](hydroxy)phosphoryl]oxy}-2-{[(2E,9E,13E)-hexadeca-2,9,13-trienoyl]oxy}propyl (4E,9E,11Z,15E)-octadeca-4,9,11,15-tetraenoate (2 entities in total)
• Functional Keywords: transporter, membrane protein
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 136152.13

Authors

Khandelwal, N.K.,Gupta, M.,Stroud, R.M. (deposition date: 2024-04-29, release date: 2025-02-05, Last modification date: 2025-08-27)

Primary citation

Khandelwal, N.K.,Gupta, M.,Gomez, J.E.,Barkho, S.,Guan, Z.,Eng, A.Y.,Kawate, T.,Balasubramani, S.G.,Sali, A.,Hung, D.T.,Stroud, R.M.
Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A.
Nat Commun, 16:3139-3139, 2025

PubMed Abstract: A broad chemical genetic screen in Mycobacterium tuberculosis (Mtb) identified compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition, we determined the structures of EfpA with these inhibitors bound at 2.7-3.4 Å resolution. Our structures reveal different mechanisms of inhibition by the two inhibitors. BRD-8000.3 binds in a tunnel contacting the lipid bilayer and extending toward the central cavity to displace the fatty acid chain of a lipid molecule bound in the apo structure, suggesting its blocking of an access route for a natural lipidic substrate. Meanwhile, BRD-9327 binds in the outer vestibule without complete blockade of the substrate path to the outside, suggesting its possible inhibition of the movement necessary for alternate access of the transporter. Our results show EfpA as a potential lipid transporter, explain the basis of the synergy of these inhibitors and their potential for combination anti-tuberculosis therapy.

PubMed: 40169593
DOI: 10.1038/s41467-025-58133-6

Experimental method

ELECTRON MICROSCOPY (3.22 Å)