7met

A. baumannii MsbA in complex with TBT1 decoupler

spinqualitylabelsall models 7met, resolution 3.97Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.97Å Ligands: Z5G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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