@article {37924,
	title = {Uracil/H Symport by FurE Refines Aspects of the Rocking-bundle Mechanism of APC-type Transporters.},
	journal = {J Mol Biol},
	volume = {435},
	year = {2023},
	month = {2023 Oct 01},
	pages = {168226},
	abstract = {Transporters mediate the uptake of solutes, metabolites and drugs across the cell membrane. The eukaryotic FurE nucleobase/H symporter of Aspergillus nidulans has been used as a model protein to address structure-function relationships in the APC transporter superfamily, members of which are characterized by the LeuT-fold and seem to operate by the so-called {\textquoteright}rocking-bundle{\textquoteright} mechanism. In this study, we reveal the binding mode, translocation and release pathway of uracil/H by FurE using path collective variable, funnel metadynamics and rational mutational analysis. Our study reveals a stepwise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that FurE, functions as a multi-step gated pore, rather than employing {\textquoteright}rocking{\textquoteright} of compact domains, as often proposed for APC transporters. Finally, our work supports that specific residues of the cytoplasmic N-tail are involved in substrate translocation, in line with their essentiality for FurE function.},
	keywords = {Biological Transport, Cell Membrane, Ion Transport, Membrane Transport Proteins, Protons, Uracil},
	issn = {1089-8638},
	doi = {10.1016/j.jmb.2023.168226},
	author = {Zantza, Iliana and Pyrris, Yiannis and Raniolo, Stefano and Papadaki, Georgia F and Lambrinidis, George and Limongelli, Vittorio and Diallinas, George and Mikros, Emmanuel}
}
