Journal
NATURE
Volume 557, Issue 7704, Pages 196-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0083-5
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Funding
- US Department of Energy (DOE)
- DOE Office of Biological and Environmental Research
- National Institute of General Medical Sciences (NIGMS)
- NIH
- Howard Hughes Medical Institute
- DOE Office of Science User Facility [DE-AC02-05CH11231]
- National Institutes of Health (NIH)
- NIGMS
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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 angstrom 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.
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