Uracil/H+ symport by the FurE transporter challenges the rocking-bundle mechanism of transport in APC transporters
Zantza, I.; Papadaki, G. F.; Raniolo, S.; Pyrris, Y.; Lambrinidis, G.; Limongelli, V.; Diallinas, G.; Mikros, E.
Show 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 rocking-bundle 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 rationally designed mutational analysis. Our study reveals a step-wise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that the FurE symporter, and probably structurally similar transporters, functions as a multi-step gated pore, rather than employing rocking of compact domains, as generally proposed for APC transporters. In addition, our work further supports the emerging concept that specific elements of cytosolic terminal regions of transporters might be functionally important.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- G Protein-Coupled Receptor-Ligand Dissociation Rates and Mechanisms from {tau}RAMD Simulations 96%
- A linear response theory based method for prediction of large scale protein conformational changes upon ligand binding 96%
- Ligand Gaussian accelerated molecular dynamics 2 (LiGaMD2): Improved calculations of ligand binding thermodynamics and kinetics with closed protein pocket 96%
Similar papers in this journal
Similar papers in this journal
- Conserved conformational hierarchy across functionally divergent glycosyltransferases of the GT-B structural superfamily as determined from microsecond molecular dynamics 95%
- Structure, function and dynamics of mCoral, a pH responsive engineered variant of the mCherry fluorescent protein with improved hydrogen peroxide tolerance. 95%
- The molecular mechanism of positive allosteric modulation at the dopamine D1 receptor 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.