Structural highlights
Function
[A0A0B9X4I2_ACIBA] Involved in lipopolysaccharide (LPS) biosynthesis. Translocates lipid A-core from the inner to the outer leaflet of the inner membrane. Transmembrane domains (TMD) form a pore in the inner membrane and the ATP-binding domain (NBD) is responsible for energy generation.[HAMAP-Rule:MF_01703]
Publication Abstract from PubMed
ATP-binding cassette (ABC) transporters couple 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. Intriguingly, two first-generation inhibitors of the MsbA transporter, 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, leading to a collapsed inward-facing conformation with decreased distance between the nucleotide-binding domains (NBDs). In contrast, two G247 molecules symmetrically increases 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.
Distinct allosteric mechanisms of first-generation MsbA inhibitors.,Thelot FA, Zhang W, Song K, Xu C, Huang J, Liao M Science. 2021 Sep 23. doi: 10.1126/science.abi9009. PMID:34554829[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Thelot FA, Zhang W, Song K, Xu C, Huang J, Liao M. Distinct allosteric mechanisms of first-generation MsbA inhibitors. Science. 2021 Sep 23. doi: 10.1126/science.abi9009. PMID:34554829 doi:http://dx.doi.org/10.1126/science.abi9009
