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-Structure paper
Title | Distinct allosteric mechanisms of first-generation MsbA inhibitors. |
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Journal, issue, pages | Science, Vol. 374, Issue 6567, Page 580-585, Year 2021 |
Publish date | Oct 29, 2021 |
Authors | François A Thélot / Wenyi Zhang / KangKang Song / Chen Xu / Jing Huang / Maofu Liao / |
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 ...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. |
External links | Science / PubMed:34554829 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.55 - 5.2 Å |
Structure data | EMDB-23803, PDB-7met: EMDB-23804, PDB-7rit: EMDB-23805, PDB-7mew: EMDB-24446: EMDB-24447: |
Chemicals | ChemComp-Z5G: ChemComp-Z5Y: |
Source |
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Keywords | MEMBRANE PROTEIN |