8YNZ

The structure of EfpA_BRD-8000.3 complex

This is a non-PDB format compatible entry.

Summary for 8YNZ

• Entry DOI: 10.2210/pdb8ynz/pdb
• EMDB information: 39432
• Descriptor: Uncharacterized MFS-type transporter EfpA, (1S,3S)-N-[6-bromo-5-(pyrimidin-2-yl)pyridin-2-yl]-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-carboxamide (2 entities in total)
• Functional Keywords: protein binding
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 120145.49

Authors

Li, D.L.,Sun, J.Q. (deposition date: 2024-03-12, release date: 2024-12-04, Last modification date: 2025-07-16)

Primary citation

Li, D.,Zhang, X.,Yao, Y.,Sun, X.,Sun, J.,Ma, X.,Yuan, K.,Bai, G.,Pang, X.,Hua, R.,Guo, T.,Mi, Y.,Wu, L.,Zhang, J.,Wu, Y.,Liu, Y.,Wang, P.,Wong, C.C.L.,Chen, X.W.,Xiao, H.,Gao, G.F.,Gao, F.
Structure and function of Mycobacterium tuberculosis EfpA as a lipid transporter and its inhibition by BRD-8000.3.
Proc.Natl.Acad.Sci.USA, 121:e2412653121-e2412653121, 2024

PubMed Abstract: EfpA, the first major facilitator superfamily (MFS) protein identified in (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA-inhibitors have been developed to kill drug-tolerant Mtb. However, the biological function of EfpA has not yet been elucidated. Here, we present the cryo-EM structures of EfpA complexed with lipids or the inhibitor BRD-8000.3 at resolutions of 2.9 Å and 3.4 Å, respectively. Unexpectedly, EfpA forms an antiparallel dimer. Functional studies reveal that EfpA is a lipid transporter and BRD-8000.3 inhibits its lipid transport activity. Intriguingly, the mutation V319F, known to confer resistance to BRD-8000.3, alters the expression level and oligomeric state of EfpA. Based on our results and the observation of other antiparallel dimers in the MFS family, we propose an antiparallel-function model of EfpA. Collectively, our work provides structural and functional insights into EfpA's role in lipid transport and drug resistance, which would accelerate the development of antibiotics against this promising drug target.

PubMed: 39441632
DOI: 10.1073/pnas.2412653121

Experimental method

ELECTRON MICROSCOPY (3.41 Å)