TCB Publications - Abstract
Jing Li and Emad Tajkhorshid. A gate-free pathway for substrate release from the inward-facing state of the Na+-galactose transporter. Biochimica et Biophysica Acta - Biomembranes, 1818:263-271, 2012.
-coupled galactose transporter,
vSGLT, have been investigated. During a 200-ns equilibrium simulation, repeated
spontaneous unbinding events of the substrate from its binding site have been observed.
In contrast to the previously proposed gating role of a tyrosine residue (Y263), the
unbinding mechanism captured in the present equilibrium simulation does not rely on the
displacement and/or rotation of this side chain. Rather, the unbinding involves an initial
lateral displacement of the substrate out of the binding site which allows the substrate to
completely emerge from the region covered by the side chain of Y263 without any
noticeable conformational changes of the latter. Starting with the snapshots taken from
this equilibrium simulation with the substrate outside the binding site, steered MD (SMD)
simulations were then used to probe the translocation of the substrate along the remaining
of the release pathway within the protein's lumen and to characterize the nature of
protein–substrate interactions involved in the process. Combining the results of the
equilibrium and SMD simulations, we provide a description of the full translocation
pathway for the substrate release from the binding site into the cytoplasm. Residues E68,
N142, T431, and N267 facilitate the initial substrate's displacement out of the binding site,
while the translocation of the substrate along the remainder of the exit pathway formed
between TM6 and TM8 is facilitated by H-bond interactions between the substrate and a
series of conserved, polar residues (Y138, N267, R273, S365, S368, N371, S372, and
T375). The observed molecular events indicate that no gating is required for the release of
the substrate from the crystallographically captured structure of the inward-facing state of
SGLT, suggesting that this conformation might represent an open, rather than occluded,
state of the transporter. This article is part of a Special Issue entitled: Membrane protein
structure and function.
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