Sequence and structural determinants of ligand-dependent alternating access of a MATE transporter
Kevin L. Jagessar, Derek P. Claxton, Richard A. Stein, Hassane S. Mchaourab
Abstract
Significance The multidrug and toxic compound extrusion (MATE) family of transporters use ion electrochemical gradients to drive the transport of cytotoxic molecules out of the cell. This work investigated how binding of protons powers the conformational changes that enable transport by PfMATE, a MATE transporter from Pyrococcus furiosus . The results show that protonation induces large-scale reconfiguration of the structure that opens the central cavity to the cytoplasm where substrate could bind. Although not previously implicated in the transport mechanism, an intracellular glutamate primarily accounts for proton sensing, facilitating isomerization from periplasmic to cytoplasmic-facing conformations. Our findings correlate conformational changes with drug resistance activity of PfMATE and offer mechanistic details of proton-coupled multidrug antiport in the MATE family of transporters.