2. Academic Validation
  3. Structural basis for dual-mode inhibition of the ABC transporter MsbA

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

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. payandeh.jian@gene.com.
  • 10 Infectious Diseases, Genentech Inc., San Francisco, CA, USA. payandeh.jian@gene.com.
  • 11 Structural Biology, Genentech Inc., San Francisco, CA, USA. koth.christopher@gene.com.
  • 12 Infectious Diseases, Genentech Inc., San Francisco, CA, USA. koth.christopher@gene.com.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125176
    98.14%, MsbA Antagonist