1p1o
From Proteopedia
(New page: 200px<br /><applet load="1p1o" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p1o, resolution 1.6Å" /> '''Crystal structure of ...) |
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| - | [[Image:1p1o.jpg|left|200px]]<br /><applet load="1p1o" size=" | + | [[Image:1p1o.jpg|left|200px]]<br /><applet load="1p1o" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1p1o, resolution 1.6Å" /> | caption="1p1o, resolution 1.6Å" /> | ||
'''Crystal structure of the GluR2 ligand-binding core (S1S2J) mutant L650T in complex with quisqualate'''<br /> | '''Crystal structure of the GluR2 ligand-binding core (S1S2J) mutant L650T in complex with quisqualate'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) | + | 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== | ==About this Structure== | ||
| - | 1P1O is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with SO4 and QUS as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1P1O is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=QUS:'>QUS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1P1O OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Armstrong, N.]] | [[Category: Armstrong, N.]] | ||
[[Category: Gouaux, E.]] | [[Category: Gouaux, E.]] | ||
| - | [[Category: Mayer, M | + | [[Category: Mayer, M L.]] |
[[Category: QUS]] | [[Category: QUS]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: ionotropic glutamate receptor]] | [[Category: ionotropic glutamate receptor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:24:09 2008'' |
Revision as of 12:24, 21 February 2008
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Crystal structure of the GluR2 ligand-binding core (S1S2J) mutant L650T in complex with quisqualate
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
1P1O is a Single protein structure of sequence from Rattus norvegicus with and 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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