Crystal Structure Analysis of MATE, a Multidrug Efflux Transporter Leading to Multidrug Resistance

Abstract

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.