Inward-facing conformation of a multidrug resistance MATE family transporter
By S. Zakrzewska, A. Mehdipour, V. N. Malviya, T. Nonaka, J. Koepke, Cornelia Muenke, Winfried Hausner, Gerhard Hummer, S. Safarian, H. Michel. 2019
47 citations recorded by the source corpus.
Significance Active efflux of drugs and toxic compounds carried out by multidrug and toxic compound extrusion (MATE) family transporters is one of the strategies developed by bacterial pathogens to confer multidrug resistance. To elucidate the underlying steps of the MATE transport cycle, structures of distinct intermediates are required; however, only structures in outward-facing conformations have been available. Our approach of using native lipids allowed trapping and visualization of the MATE transporter from Pyrococcus furiosus in an inward-facing conformation. This work highlights the importance of native lipids and opens an alternative view on the function and mechanism of action for the MATE family transporters. Multidrug and toxic compound extrusion (MATE) transporters mediate excretion of xenobiotics and toxic metabolites, thereby conferring multidrug resistance in bacterial pathogens and cancer cells. Structural information on the alternate conformational states and knowledge of the detailed mechanism of MATE transport are of great importance for drug development. However, the structures of MATE transporters are only known in V-shaped outward-facing conformations. Here, we present the crystal structure of a MATE transporter from Pyrococcus furiosus (PfMATE) in the long-sought-after inward-facing state, which was obtained after crystallization in the presence of native lipids. Transition from the outward-facing state to the inward-facing state involves rigid body movements of transmembrane helices (TMs) 2–6 and 8–12 to form an inverted V, facilitated by a loose binding of TM1 and TM7 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 the MATE family transporters.
Subfields: Genetics, Materials Chemistry, Molecular Medicine
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Citations in the corpus
- Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, background): “…the class A GPCR CCR5 ( Zheng et al., 2017 ; Zhang et al., 2021 ), the serotonin transporter SERT ( Coleman et al., 2016 ; Coleman et al., 2019 ), the multidrug transporter PfMATE ( Tanaka et al., 2013 ; Zakrzewska et al., 2019 ), and the lipid flippase MurJ ( Kuk et al., 2017 ; Kuk et al., 2019 ).”