Structural basis for dual-mode inhibition of the ABC transporter MsbA

Hoangdung Ho, Anh Miu, Mary Kate Alexander, Natalie K. Garcia, Angela Oh, Inna Zilberleyb, Mike Reichelt, Cary D. Austin, Christine Tam, Stephanie Shriver, Huiyong Hu, Sharada S. Labadie, Jun Liang, Lan Wang, Jian Wang, Yan Lu, Hans E. Purkey, John Quinn, Yvonne Franke, Kevin Clark, Maureen H. Beresini, Man-Wah Tan, Benjamin D. Sellers, Till Maurer, Michael F. T. Koehler, Aaron T. Wecksler, James R. Kiefer, Vishal Verma, Yiming Xu, Mireille Nishiyama, Jian Payandeh () and Christopher M. Koth ()
Additional contact information
Hoangdung Ho: Genentech Inc.
Anh Miu: Genentech Inc.
Mary Kate Alexander: Genentech Inc.
Natalie K. Garcia: Genentech Inc.
Angela Oh: Genentech Inc.
Inna Zilberleyb: Genentech Inc.
Mike Reichelt: Genentech Inc.
Cary D. Austin: Genentech Inc.
Christine Tam: Genentech Inc.
Stephanie Shriver: Genentech Inc.
Huiyong Hu: Genentech Inc.
Sharada S. Labadie: Genentech Inc.
Jun Liang: Genentech Inc.
Lan Wang: Genentech Inc.
Jian Wang: WuXi Apptec. Co. Ltd.
Yan Lu: WuXi Apptec. Co. Ltd.
Hans E. Purkey: Genentech Inc.
John Quinn: Genentech Inc.
Yvonne Franke: Genentech Inc.
Kevin Clark: Genentech Inc.
Maureen H. Beresini: Genentech Inc.
Man-Wah Tan: Genentech Inc.
Benjamin D. Sellers: Genentech Inc.
Till Maurer: Genentech Inc.
Michael F. T. Koehler: Genentech Inc.
Aaron T. Wecksler: Genentech Inc.
James R. Kiefer: Genentech Inc.
Vishal Verma: Genentech Inc.
Yiming Xu: Genentech Inc.
Mireille Nishiyama: Genentech Inc.
Jian Payandeh: Genentech Inc.
Christopher M. Koth: Genentech Inc.

Nature, 2018, vol. 557, issue 7704, 196-201

Abstract: Abstract 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 Å 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.

Date: 2018
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DOI: 10.1038/s41586-018-0083-5

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