3.A.1.106.18
Peptide and multidrug resistance porter of the ABC superfamily, TmrAB. TmrA (Q72J05; 600 aas with 6 N-terminal TMSs) and TmrB (Q72J04; 578 aas with 6 N-terminal TMSs) comprise this heterodimeric transporter, both proteins of the M-C structure.  The system has been found to export the dye, hoechst 33342, and to be inhibited by verapamil (Zutz et al. 2011). The subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle electron cryomicroscopy has been solved (Kim et al. 2015). A cavity in the transmembrane domain is accessible laterally from the cytoplasmic side of the membrane as well as from the cytoplasm, indicating that the transporter lies in an inward-facing open conformation. The two nucleotide-binding domains remain in contact via their carboxy-terminal helices. Comparison between this structure and those of other ABC transporters suggests a possible trajectory of conformational changes that involves a sliding and rotating motion between the two nucleotide-binding domains during the transition from the inward-facing to outward-facing conformations (Kim et al. 2015). A subset of annular lipids is normally invariant in composition, with negatively charged lipids binding tightly to TmrAB, suggesting that this exporter may be involved in glycolipid translocation (Bechara et al. 2015). Coupled ATPase-adenylate kinase activity in ABC transporters including TmrAB has been demonstrated (Kaur et al. 2016). A 2.7-Å X-ray structure of TmrAB has been determined. It not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. It adopts an asymmetric inward-facing state, and the C-terminal helices, arranged in a zipper-like fashion, play a role in guiding the conformational changes associated with substrate transport (Nöll et al. 2017). Conformational coupling and trans-inhibition have been characterized (Barth et al. 2018), and a  conserved motif in intracellular loop 1 stabilizes the outward-facing conformation of TmrAB (Millan et al. 2021). A strong entropy-enthalpy compensation mechanism enables the closure of the nucleotide-binding domains (NBDs) over a wide temperature range. This is mechanically coupled with an outward opening of the transmembrane domains (TMDs) accompanied by an entropy gain (Barth et al. 2020).  TmrAB undergoes a reversible transition in the presence of ATP with a significantly faster forward transition. The impaired degenerate NBS stably binds Mn²⁺-ATP, and Mn²⁺ is preferentially released at the active consensus NBS (Rudolf et al. 2023). ATP hydrolysis at the consensus NBS considerably accelerates the reverse transition. Both NBSs fully open during each conformational cycle, and the degenerate NBS may regulate the kinetics of this process (Rudolf et al. 2023).