2. Academic Validation
  3. Distinct allosteric mechanisms of first-generation MsbA inhibitors

Distinct allosteric mechanisms of first-generation MsbA inhibitors

  • Science. 2021 Oct 29;374(6567):580-585. doi: 10.1126/science.abi9009.
François A Thélot 1 2,  Wenyi Zhang 3 4,  KangKang Song 5 6,  Chen Xu 5 6,  Jing Huang 3 4,  Maofu Liao 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Biological and Biomedical Sciences Program, Harvard University, Cambridge, MA, USA.
  • 3 Key Laboratory of Structural Biology of Zhejiang Province, Westlake University, Hangzhou, China.
  • 4 Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
  • 5 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
  • 6 Cryo-EM Core Facility, University of Massachusetts Medical School, Worcester, MA, USA.
PMID: 34554829 DOI: 10.1126/science.abi9009
Abstract

ATP-binding cassette (ABC) transporters couple adenosine 5′-triphosphate (ATP) hydrolysis to substrate transport across biological membranes. Although many are promising drug targets, their mechanisms of modulation by small-molecule inhibitors remain largely unknown. Two first-generation inhibitors of the MsbA transporter, tetrahydrobenzothiophene 1 (TBT1) and G247, induce opposite effects on ATP hydrolysis. Using single-particle cryo–electron microscopy and functional assays, we show that TBT1 and G247 bind adjacent yet separate pockets in the MsbA transmembrane domains. Two TBT1 molecules asymmetrically occupy the substrate-binding site, which leads to a collapsed inward-facing conformation with decreased distance between the nucleotide-binding domains (NBDs). By contrast, two G247 molecules symmetrically increase NBD distance in a wide inward-open state of MsbA. The divergent mechanisms of action of these MsbA inhibitors provide important insights into ABC transporter pharmacology.

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