6bpp

Publication Abstract from PubMed

The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 A resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.

Structural basis for dual-mode inhibition of the ABC transporter MsbA.,Ho H, Miu A, Alexander MK, Garcia NK, Oh A, Zilberleyb I, Reichelt M, Austin CD, Tam C, Shriver S, Hu H, Labadie SS, Liang J, Wang L, Wang J, Lu Y, Purkey HE, Quinn J, Franke Y, Clark K, Beresini MH, Tan MW, Sellers BD, Maurer T, Koehler MFT, Wecksler AT, Kiefer JR, Verma V, Xu Y, Nishiyama M, Payandeh J, Koth CM Nature. 2018 May 2. pii: 10.1038/s41586-018-0083-5. doi:, 10.1038/s41586-018-0083-5. PMID:29720648^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.