Probing the Allosteric NBD-TMD Crosstalk in the ABC Transporter MsbA by Solid-state NMR
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The ABC transporter MsbA plays a critical role in Gram-negative bacteria in the regulation of the outer membrane by translocating core-LPS across the inner membrane. Additionally, a broad substrate specificity for lipophilic drugs has been shown. The allosteric interplay between substrate binding in the transmembrane domains and ATP binding and turnover in the nucleotide-binding domains must be mediated via the NBD/TMD interface. Previous studies suggested the involvement of two intracellular loops called coupling helix 1 and 2 (CH1, CH2). Here, we demonstrate by solid-state NMR spectroscopy that substantial chemical shift changes within both CH1 and CH2 occur upon substrate binding, in the ATP hydrolysis transition state, and upon inhibitor binding. CH2 is domain-swapped within the MsbA structure, and it is noteworthy that substrate binding induces a larger response in CH2 compared to CH1. Our data demonstrate that CH1 and CH2 undergo structural changes as part of the TMD-NBD cross-talk.
Rhodamine6G and Hœchst33342 narrow BmrA conformational spectrum for a more efficient use of ATP.
Gobet A, Moissonnier L, Zarkadas E, Magnard S, Bettler E, Martin J Nat Commun. 2025; 16(1):1745.
PMID: 39966360 PMC: 11836358. DOI: 10.1038/s41467-025-56849-z.