2.A.66.1.55
MATE drug:sodium symporter of 461 aas and 12 TMSs.  Several crystal structures are known (3VVO, 3VVP, 3VVR, 3VVS, 6FHZ, 6GWH) in several distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 1.8 - 3.0 Å resolutions. The structures, combined with functional analyses, showed that the protonation of Asp 41 on the N-terminal lobe induces the bending of TMS1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities (Tanaka et al. 2013). The  Na⁺-binding site, in the N-lobe of this transporter, is selective against K⁺, weakly specific against H⁺, and broadly conserved among prokaryotic MATEs (Ficici et al. 2018). The inward-facing state was obtained after crystallization in the presence of native lipids (Zakrzewska et al. 2019). The transition from the outward-facing state to the inward-facing state involves rigid body movements of TMSs 2-6 and 8-12 to form an inverted V, facilitated by a loose binding of TMS1 and TMS7 to their respective bundles and their conformational flexibility. The inward-facing structure of PfMATE in combination with the outward-facing one supports an alternating access mechanism for MATE family transporters (Zakrzewska et al. 2019).