7RIT

Drug-free A. baumannii MsbA

Summary for 7RIT

• Entry DOI: 10.2210/pdb7rit/pdb
• EMDB information: 23804
• Descriptor: ATP-dependent lipid A-core flippase (1 entity in total)
• Functional Keywords: membrane protein
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 2
• Total formula weight: 135517.38

Authors

Thelot, F.,Liao, M. (deposition date: 2021-07-20, release date: 2021-10-06, Last modification date: 2024-06-05)

Primary citation

Thelot, F.A.,Zhang, W.,Song, K.,Xu, C.,Huang, J.,Liao, M.
Distinct allosteric mechanisms of first-generation MsbA inhibitors.
Science, 374:580-585, 2021

PubMed 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.

PubMed: 34554829
DOI: 10.1126/science.abi9009

Experimental method

ELECTRON MICROSCOPY (5.2 Å)