Structural changes and xylose docking to eight conformers of Escherichia Coli XylE, a xylose transporter similar to mammalian passive glucose transporters GLUTs, have been examined. Xylose docks to inward and outward facing conformers at a high affinity central site (K i 4–20 µM), previously identified by crystallography and additionally consistently docks to lower affinity sites in the external and internal vestibules (K i 12–50 µM). All these sites lie within intramolecular tunnels and cavities. Several local regions in the central transmembrane zone have large positional divergences of both skeleton carbon Cα positions and side chains. One such in TM 10 is the destabilizing sequence G388-P389-V390-C391 with an average RMSD (4.5 ± 0.4 Å). Interchange between conformer poses results in coalescence of tunnels with adjacent cavities, thereby producing a transitory channel spanning the entire transporter. A fully open channel exists in one inward-facing apo-conformer, (PDB 4ja4c) as demonstrated by several different tunnel-finding algorithms. The conformer interchanges produce a gated network within a branched central channel that permits staged ligand diffusion across the transporter during the open gate periods. Simulation of this model demonstrates that small-scale conformational changes required for sequentially opening gate with frequencies in the ns-μs time domain accommodate diffusive ligand flow between adjacent sites with association–dissociation rates in the μs-ms domain without imposing delays. This current model helps to unify the apparently opposing concepts of alternate access and multisite models of ligand transport.
The Journal of Membrane Biology – Springer Journals
Published: Aug 28, 2014
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