9s2u
1:1 complex of M.tuberculosis MmpL5 and M.smegmatis AcpM
Structural highlights
FunctionMMPL5_MYCTU Part of an export system, which is required for biosynthesis and secretion of siderophores.[1] Overexpression of the system confers non-target based resistance to azoles, clofazimine and bedaquiline, via an efflux mechanism.[2] [3] [4] GFP_AEQVI Energy-transfer acceptor. Its role is to transduce the blue chemiluminescence of the protein aequorin into green fluorescent light by energy transfer. Fluoresces in vivo upon receiving energy from the Ca(2+)-activated photoprotein aequorin. Publication Abstract from PubMedBedaquiline, an antitubercular drug that targets ATP-synthase, is a key component of a new oral drug regimen that has revolutionized the treatment of multidrug-resistant tuberculosis. Clinical bedaquiline resistance in Mycobacterium tuberculosis has rapidly emerged, primarily due to mutations in the transcriptional repressor Rv0678 that result in upregulation of the resistance-nodulation-division (RND) efflux pump MmpS5/MmpL5 (MmpS5L5). Here, to understand how MmpS5L5 effluxes bedaquiline, we determined the structure of the MmpS5L5 complex using cryo-electron microscopy, revealing a trimeric architecture distinct from the canonical tripartite RND efflux pumps of gram-negative bacteria. Structure prediction modeling in conjunction with functional genetic analysis indicates that it uses a periplasmic coiled-coil tube to transport molecules across the cell wall. Structure-guided genetic approaches identify MmpL5 mutations that alter bedaquiline transport; these mutations converge on a region in MmpL5 located in the lower portion of the periplasmic cavity, proximal to the outer leaflet of the inner membrane, suggesting a route for bedaquiline entry into the pump. While currently known clinical resistance to bedaquiline is due to pump upregulation, our findings that several MmpL5 variants increase bedaquiline efflux may presage the emergence of additional modes of clinical resistance. Structural and functional analysis of the Mycobacterium tuberculosis MmpS5L5 efflux pump presages increased bedaquiline resistance.,Fountain AJ, Bohning J, McLaughlin SH, Morgan TE, Edelstein PH, Troll M, Lamers MH, Bharat TAM, Luisi BF, Ramakrishnan L Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2516660122. doi: , 10.1073/pnas.2516660122. Epub 2025 Sep 23. PMID:40986343[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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