1n0t: Difference between revisions

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OCA

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-[[Image:1n0t.jpg|left|200px]]<br /><applet load="1n0t" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1n0t, resolution 2.10&Aring;" />
-'''X-ray structure of the GluR2 ligand-binding core (S1S2J) in complex with the antagonist (S)-ATPO at 2.1 A resolution.'''<br />
-==Overview==
+==X-ray structure of the GluR2 ligand-binding core (S1S2J) in complex with the antagonist (S)-ATPO at 2.1 A resolution.==
-Ionotropic glutamate receptors (iGluRs) constitute a family of, ligand-gated ion channels that are essential for mediating fast synaptic, transmission in the central nervous system. This study presents a, high-resolution X-ray structure of the competitive antagonist, (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic, acid (ATPO) in complex with the ligand-binding core of the receptor., Comparison with the only previous structure of the ligand-binding core in, complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX), (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO, and DNQX stabilize an open form of the ligand-binding core by different, sets of interactions. Computational techniques are used to quantify the, differences between these two ligands and to map the binding site. The, isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds, could potentially be used. Whereas agonists induce substantial domain, closures compared to the apo structure, ATPO only induces minor, conformational changes. These results are consistent with the hypothesis, that domain closure is related to receptor activation. To facilitate the, design of novel AMPA receptor antagonists, we present a modified model of, the binding site that includes key residues involved in ligand, recognition.
+<StructureSection load='1n0t' size='340' side='right'caption='[[1n0t]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1n0t]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N0T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1N0T FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AT1:(S)-2-AMINO-3-(5-TERT-BUTYL-3-(PHOSPHONOMETHOXY)-4-ISOXAZOLYL)PROPIONIC+ACID'>AT1</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1n0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1n0t OCA], [https://pdbe.org/1n0t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1n0t RCSB], [https://www.ebi.ac.uk/pdbsum/1n0t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1n0t ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/GRIA2_RAT GRIA2_RAT] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.<ref>PMID:9351977</ref> <ref>PMID:19265014</ref> <ref>PMID:21172611</ref> <ref>PMID:12501192</ref> <ref>PMID:12015593</ref> <ref>PMID:12872125</ref> <ref>PMID:12730367</ref> <ref>PMID:16192394</ref> <ref>PMID:15591246</ref> <ref>PMID:17018279</ref> <ref>PMID:16483599</ref> <ref>PMID:19946266</ref> <ref>PMID:21317873</ref> <ref>PMID:21846932</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/n0/1n0t_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1n0t ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.
-==About this Structure==
+Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX.,Hogner A, Greenwood JR, Liljefors T, Lunn ML, Egebjerg J, Larsen IK, Gouaux E, Kastrup JS J Med Chem. 2003 Jan 16;46(2):214-21. PMID:12519060<ref>PMID:12519060</ref>
-N0T 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, ACT and AT1 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1N0T OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX., Hogner A, Greenwood JR, Liljefors T, Lunn ML, Egebjerg J, Larsen IK, Gouaux E, Kastrup JS, J Med Chem. 2003 Jan 16;46(2):214-21. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12519060 12519060]
+</div>
+<div class="pdbe-citations 1n0t" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Rattus norvegicus]]
-[[Category: Single protein]]
+[[Category: Egebjerg J]]
-[[Category: Egebjerg, J.]]
+[[Category: Gouaux E]]
-[[Category: Gouaux, E.]]
+[[Category: Greenwood JR]]
-[[Category: Greenwood, J.R.]]
+[[Category: Hogner A]]
-[[Category: Hogner, A.]]
+[[Category: Kastrup JS]]
-[[Category: Kastrup, J.S.]]
+[[Category: Larsen IK]]
-[[Category: Larsen, I.K.]]
+[[Category: Liljefors T]]
-[[Category: Liljefors, T.]]
+[[Category: Lunn M-L]]
-[[Category: Lunn, M.L.]]
-[[Category: ACT]]
-[[Category: AT1]]
-[[Category: SO4]]
-[[Category: antagonist complex]]
-[[Category: ionotropic glutamate receptor glur2]]
-[[Category: ligand-binding core]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 21:51:33 2007''