7m33

The structure of Bacillus subtilis BmrCD in the inward-facing conformation bound to Hoechst-33342 and ATP

spinqualitylabelsall models 7m33, resolution 3.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7m33 is a 2 chain structure with sequence from Bacillus subtilis subsp. subtilis str. 168. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.55Å Ligands: ATP, HT1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function YHEI_BACSU Involved in the transport of four structurally unrelated drugs, including doxorubicin and mitoxantrone. Transmembrane domains (TMD) form a pore in the membrane and the ATP-binding domain (NBD) is responsible for energy generation. Publication Abstract from PubMed Substrate efflux by ATP-binding cassette (ABC) transporters, which play a major role in multidrug resistance, entails the ATP-powered interconversion between transporter intermediates. Despite recent progress in structure elucidation, a number of intermediates have yet to be visualized and mechanistically interpreted. Here, we combine cryogenic-electron microscopy (cryo-EM), double electron-electron resonance spectroscopy and molecular dynamics simulations to profile a previously unobserved intermediate of BmrCD, a heterodimeric multidrug ABC exporter from Bacillus subtilis. In our cryo-EM structure, ATP-bound BmrCD adopts an inward-facing architecture featuring two molecules of the substrate Hoechst-33342 in a striking asymmetric head-to-tail arrangement. Deletion of the extracellular domain capping the substrate-binding chamber or mutation of Hoechst-coordinating residues abrogates cooperative stimulation of ATP hydrolysis. Together, our findings support a mechanistic role for symmetry mismatch between the nucleotide binding and the transmembrane domains in the conformational cycle of ABC transporters and is of notable importance for rational design of molecules for targeted ABC transporter inhibition. Asymmetric drug binding in an ATP-loaded inward-facing state of an ABC transporter.,Thaker TM, Mishra S, Zhou W, Mohan M, Tang Q, Faraldo-Gomez JD, Mchaourab HS, Tomasiak TM Nat Chem Biol. 2022 Feb;18(2):226-235. doi: 10.1038/s41589-021-00936-x. Epub 2021 , Dec 20. PMID:34931066 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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