Salt-bridge dynamics control substrate-induced conformational change in the membrane transporter GlpT |
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Authors: | Law Christopher J Almqvist Jonas Bernstein Adam Goetz Regina M Huang Yafei Soudant Celine Laaksonen Aatto Hovmöller Sven Wang Da-Neng |
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Institution: | 1 The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA 2 Division of Structural Chemistry, Arrhenius Laboratory, Stockholm University, S-10691 Stockholm, Sweden 3 Department of Molecular Biology, Uppsala Biomedical Center, Swedish University of Agricultural Sciences, Box 590, S-753 24 Uppsala, Sweden 4 Division of Physical Chemistry, Arrhenius Laboratory, Stockholm University, S-10691 Stockholm, Sweden |
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Abstract: | Active transport of substrates across cytoplasmic membranes is of great physiological, medical and pharmaceutical importance. The glycerol-3-phosphate (G3P) transporter (GlpT) of the E. coli inner membrane is a secondary active antiporter from the ubiquitous major facilitator superfamily that couples the import of G3P to the efflux of inorganic phosphate (Pi) down its concentration gradient. Integrating information from a novel combination of structural, molecular dynamics simulations and biochemical studies, we identify the residues involved directly in binding of substrate to the inward-facing conformation of GlpT, thus defining the structural basis for the substrate-specificity of this transporter. The substrate binding mechanism involves protonation of a histidine residue at the binding site. Furthermore, our data suggest that the formation and breaking of inter- and intradomain salt bridges control the conformational change of the transporter that accompanies substrate translocation across the membrane. The mechanism we propose may be a paradigm for organophosphate:phosphate antiporters. |
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Keywords: | G3P sn-glycerol 3-phosphate GlpT G3P transporter OPA organophosphate/phosphate antiporter G6PT glucose 6-phosphate transporter MFS major facilitator superfamily |
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