3.A.1.106.8
The heterodimeric BmrC/BmrD (YheHI) MDR transporter.  Transports a wide range of structurally unrelated drugs including doxorubicin, mitoxantrone, ethidium, and hoechst 33342 (Torres et al., 2009). It activates the sensor kinase, KinA, during sporulation initiation (Fukushima et al. 2006). Large scale purification has been achieved (Galián et al. 2011).  It has been reconstituted in giant unilamellar vesicles (Dezi et al. 2013).  It exhibits an asymmetric configuration of catalytically inequivalent nucleotide binding sites. The two-state transition of the TMS domains, from an inward- to an outward-facing conformation, may be driven exclusively by ATP hydrolysis (Mishra et al. 2014). A novel intermediate of BmrCD, a heterodimeric multidrug ABC exporter from Bacillus subtilis. has been identified (Thaker et al. 2021). In the cryo-EM structure, ATP-bound BmrCD adopts an inward-facing architecture featuring two molecules of the substrate Hoechst-33342 in an 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. These findings support a mechanistic role for symmetry mismatch between the nucleotide binding and the transmembrane domains in the conformational cycle of ABC transporters (Thaker et al. 2021). Lipid interactions with BmrCD modulate the energy landscape, suggesting a distinct transport model that highlights the role of asymmetric conformations in the ATP-coupled cycle with implications to the mechanism of ABC transporters in general (Tang et al. 2023).