1p1w
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(New page: 200px<br /><applet load="1p1w" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p1w, resolution 1.80Å" /> '''Crystal structure of...)
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Revision as of 21:16, 20 November 2007
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Crystal structure of the GluR2 ligand-binding core (S1S2J) with the L483Y and L650T mutations and in complex with AMPA
Overview
The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA), receptor discriminates between agonists in terms of binding and channel, gating; AMPA is a high-affinity full agonist, whereas kainate is a, low-affinity partial agonist. Although there is extensive literature on, the functional characterization of partial agonist activity in ion, channels, structure-based mechanisms are scarce. Here we investigate the, role of Leu-650, a binding cleft residue conserved among AMPA receptors, in maintaining agonist specificity and regulating agonist binding and, channel gating by using physiological, x-ray crystallographic, and, biochemical techniques. Changing Leu-650 to Thr yields a receptor that, responds more potently and efficaciously to kainate and less potently and, efficaciously to AMPA relative to the WT receptor. Crystal structures of, the Leu-650 to Thr mutant reveal an increase in domain closure in the, kainate-bound state and a partially closed and a fully closed conformation, in the AMPA-bound form. Our results indicate that agonists can induce a, range of conformations in the GluR2 ligand-binding core and that domain, closure is directly correlated to channel activation. The partially, closed, AMPA-bound conformation of the L650T mutant likely captures the, structure of an agonist-bound, inactive state of the receptor. Together, with previously solved structures, we have determined a mechanism of, agonist binding and subsequent conformational rearrangements.
About this Structure
1P1W is a Single protein structure of sequence from Rattus norvegicus with SO4 and AMQ as ligands. Full crystallographic information is available from OCA.
Reference
Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes., Armstrong N, Mayer M, Gouaux E, Proc Natl Acad Sci U S A. 2003 May 13;100(10):5736-41. Epub 2003 May 2. PMID:12730367
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