Structure of a cation-bound multidrug and toxic compound extrusion transporter

Abstract

Transporter proteins from the MATE (multidrug and toxic compound extrusion) family are involved in metabolite transport in plants and in multidrug resistance in bacteria and mammals. MATE transporters were the only remaining class of multidrug resistance transporter whose structure was not known. The X-ray structure of a prototypical MATE protein, NorM from Vibrio cholerae, has now been determined to 3.65 Å resolution, revealing a protein topology distinct from other membrane-protein structures solved to date. The structure is in an 'outward-facing' conformation, with a cation-binding site in close proximity to residues previously deemed critical for transport. Transporter proteins from the MATE (multidrug and toxic compound extrusion) family are involved in metabolite transport in plants, and in multiple-drug resistance in bacteria and mammals. Here, the X-ray crystal structure of a MATE transporter from Vibrio cholerae is reported. The structure is in an outward-facing conformation, and reveals a cation-binding site near to residues previously deemed essential for transport. Transporter proteins from the MATE (multidrug and toxic compound extrusion)1 family are vital in metabolite transport in plants2,3, directly affecting crop yields worldwide4. MATE transporters also mediate multiple-drug resistance (MDR) in bacteria and mammals5, modulating the efficacy of many pharmaceutical drugs used in the treatment of a variety of diseases6,7,8,9. MATE transporters couple substrate transport to electrochemical gradients and are the only remaining class of MDR transporters whose structure has not been determined10. Here we report the X-ray structure of the MATE transporter NorM from Vibrio cholerae determined to 3.65 Å, revealing an outward-facing conformation with two portals open to the outer leaflet of the membrane and a unique topology of the predicted 12 transmembrane helices distinct from any other known MDR transporter. We also report a cation-binding site in close proximity to residues previously deemed critical for transport11. This conformation probably represents a stage of the transport cycle with high affinity for monovalent cations and low affinity for substrates.