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

  • Nature. 2018 May;557(7704):196-201. doi: 10.1038/s41586-018-0083-5.
Hoangdung Ho  1 ,  Anh Miu  2 ,  Mary Kate Alexander  3 ,  Natalie K Garcia  4 ,  Angela Oh  1 ,  Inna Zilberleyb  5 ,  Mike Reichelt  6 ,  Cary D Austin  6 ,  Christine Tam  5 ,  Stephanie Shriver  5 ,  Huiyong Hu  7 ,  Sharada S Labadie  7 ,  Jun Liang  7 ,  Lan Wang  7 ,  Jian Wang  8 ,  Yan Lu  8 ,  Hans E Purkey  7 ,  John Quinn  2 ,  Yvonne Franke  5 ,  Kevin Clark  2 ,  Maureen H Beresini  2 ,  Man-Wah Tan  3 ,  Benjamin D Sellers  7 ,  Till Maurer  1 ,  Michael F T Koehler  7 ,  Aaron T Wecksler  4 ,  James R Kiefer  1 ,  Vishal Verma  7 ,  Yiming Xu  2 ,  Mireille Nishiyama  3 ,  Jian Payandeh  9  10 ,  Christopher M Koth  11  12
Affiliations
  • 1. Structural Biology, Genentech Inc., San Francisco, CA, USA.
  • 2. Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA.
  • 3. Infectious Diseases, Genentech Inc., San Francisco, CA, USA.
  • 4. Protein Analytical Chemistry, Genentech Inc., San Francisco, CA, USA.
  • 5. Biomolecular Resources, Genentech Inc., San Francisco, CA, USA.
  • 6. Pathology, Genentech Inc., San Francisco, CA, USA.
  • 7. Discovery Chemistry, Genentech Inc., San Francisco, CA, USA.
  • 8. WuXi Apptec. Co. Ltd., Shanghai, China.
  • 9. Structural Biology, Genentech Inc., San Francisco, CA, USA. [email protected].
  • 10. Infectious Diseases, Genentech Inc., San Francisco, CA, USA. [email protected].
  • 11. Structural Biology, Genentech Inc., San Francisco, CA, USA. [email protected].
  • 12. Infectious Diseases, Genentech Inc., San Francisco, CA, USA. [email protected].
PMID: 29720648 DOI: 10.1038/s41586-018-0083-5
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.

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