薬剤耐性病原菌出現の原因となる多剤排出輸送体MATEの結晶構造解析

抄録

MATE （multidrug and toxic compound extrusion） family transporters are conserved in the three primary kingdoms, and export xenobiotics using an electrochemical gradient of H⁺ or Na⁺ across the membrane.¹⁾ MATE transporters confer multidrug resistance （MDR） to bacterial pathogens²⁾ and cancer cells.³⁾ Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine.⁴⁾ Here we present the crystal structures of the H⁺-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides. The structures, combined with functional analyses, revealed that the protonation of Asp41 on the N-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extra-cellular space. Moreover, two of the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities.