2al4: Difference between revisions
New page: left|200px<br /><applet load="2al4" size="450" color="white" frame="true" align="right" spinBox="true" caption="2al4, resolution 1.70Å" /> '''CRYSTAL STRUCTURE OF... |
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[[Image:2al4.gif|left|200px]]<br /><applet load="2al4" size=" | [[Image:2al4.gif|left|200px]]<br /><applet load="2al4" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2al4, resolution 1.70Å" /> | caption="2al4, resolution 1.70Å" /> | ||
'''CRYSTAL STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH quisqualate and CX614.'''<br /> | '''CRYSTAL STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH quisqualate and CX614.'''<br /> | ||
==Overview== | ==Overview== | ||
Ligand-gated ion channels involved in the modulation of synaptic strength | Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation. | ||
==About this Structure== | ==About this Structure== | ||
2AL4 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 ZN, CX6 and QUS as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 2AL4 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=ZN:'>ZN</scene>, <scene name='pdbligand=CX6:'>CX6</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=2AL4 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Clark, S.]] | [[Category: Clark, S.]] | ||
[[Category: Dudman, J | [[Category: Dudman, J T.]] | ||
[[Category: Gouaux, E.]] | [[Category: Gouaux, E.]] | ||
[[Category: Jin, R.]] | [[Category: Jin, R.]] | ||
[[Category: Partin, K | [[Category: Partin, K M.]] | ||
[[Category: Weeks, A | [[Category: Weeks, A M.]] | ||
[[Category: CX6]] | [[Category: CX6]] | ||
[[Category: QUS]] | [[Category: QUS]] | ||
| Line 30: | Line 30: | ||
[[Category: s1s2]] | [[Category: s1s2]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:28:30 2008'' | ||
Revision as of 17:28, 21 February 2008
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CRYSTAL STRUCTURE OF THE GLUR2 LIGAND BINDING CORE (S1S2J) IN COMPLEX WITH quisqualate and CX614.
OverviewOverview
Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.
About this StructureAbout this Structure
2AL4 is a Single protein structure of sequence from Rattus norvegicus with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Mechanism of positive allosteric modulators acting on AMPA receptors., Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM, J Neurosci. 2005 Sep 28;25(39):9027-36. PMID:16192394
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