4gxs

From Proteopedia

(Difference between revisions)

Current revision

Ligand binding domain of GluA2 (AMPA/glutamate receptor) bound to (-)-kaitocephalin

Structural highlights

4gxs is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9634Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14]

Publication Abstract from PubMed

Glutamate receptors mediate the majority of excitatory synaptic transmission in the central nervous system and excessive stimulation of these receptors is involved in a variety of neurological disorders and neuronal damage from stroke. The development of new subtype specific antagonists would be of considerable therapeutic interest. Natural products can provide important new lead compounds for drug discovery. The only natural product known to inhibit glutamate receptors competitively is (-)-kaitocephalin, which was isolated from the fungus, Eupenicillium shearii and found to protect CNS neurons from excitotoxicity. Previous work has shown that it is a potent antagonist of some subtypes of glutamate receptors (AMPA and NMDA, but not kainate). The structure of kaitocephalin bound to the ligand-binding domain of the AMPA receptor subtype, GluA2, is reported here. The structure suggests how kaitocephalin can be used as a scaffold to develop more selective and high affinity antagonists for glutamate receptors.

The Structure of (-)-Kaitocephalin Bound to the Ligand Binding Domain of the AMPA/Glutamate Receptor, GluA2.,Ahmed AH, Hamada M, Shinada T, Ohfune Y, Weerasinghe L, Garner PP, Oswald RE J Biol Chem. 2012 Oct 17. PMID:23076153^[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Everts I, Villmann C, Hollmann M. N-Glycosylation is not a prerequisite for glutamate receptor function but Is essential for lectin modulation. Mol Pharmacol. 1997 Nov;52(5):861-73. PMID:9351977
↑ Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler B, Klocker N. Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science. 2009 Mar 6;323(5919):1313-9. doi: 10.1126/science.1167852. PMID:19265014 doi:10.1126/science.1167852
↑ Kato AS, Gill MB, Ho MT, Yu H, Tu Y, Siuda ER, Wang H, Qian YW, Nisenbaum ES, Tomita S, Bredt DS. Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins. Neuron. 2010 Dec 22;68(6):1082-96. doi: 10.1016/j.neuron.2010.11.026. PMID:21172611 doi:10.1016/j.neuron.2010.11.026
↑ Jin R, Horning M, Mayer ML, Gouaux E. Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate. Biochemistry. 2002 Dec 31;41(52):15635-43. PMID:12501192
↑ Sun Y, Olson R, Horning M, Armstrong N, Mayer M, Gouaux E. Mechanism of glutamate receptor desensitization. Nature. 2002 May 16;417(6886):245-53. PMID:12015593 doi:10.1038/417245a
↑ Jin R, Banke TG, Mayer ML, Traynelis SF, Gouaux E. Structural basis for partial agonist action at ionotropic glutamate receptors. Nat Neurosci. 2003 Aug;6(8):803-10. PMID:12872125 doi:10.1038/nn1091
↑ Armstrong N, Mayer M, Gouaux E. Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5736-41. Epub 2003 May 2. PMID:12730367 doi:http://dx.doi.org/10.1073/pnas.1037393100
↑ Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM. Mechanism of positive allosteric modulators acting on AMPA receptors. J Neurosci. 2005 Sep 28;25(39):9027-36. PMID:16192394 doi:25/39/9027
↑ Frandsen A, Pickering DS, Vestergaard B, Kasper C, Nielsen BB, Greenwood JR, Campiani G, Fattorusso C, Gajhede M, Schousboe A, Kastrup JS. Tyr702 is an important determinant of agonist binding and domain closure of the ligand-binding core of GluR2. Mol Pharmacol. 2005 Mar;67(3):703-13. Epub 2004 Dec 9. PMID:15591246 doi:10.1124/mol.104.002931
↑ Armstrong N, Jasti J, Beich-Frandsen M, Gouaux E. Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor. Cell. 2006 Oct 6;127(1):85-97. PMID:17018279 doi:10.1016/j.cell.2006.08.037
↑ Kasper C, Pickering DS, Mirza O, Olsen L, Kristensen AS, Greenwood JR, Liljefors T, Schousboe A, Watjen F, Gajhede M, Sigurskjold BW, Kastrup JS. The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. J Mol Biol. 2006 Apr 7;357(4):1184-201. Epub 2006 Jan 31. PMID:16483599 doi:10.1016/j.jmb.2006.01.024
↑ Sobolevsky AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009 Dec 10;462(7274):745-56. Epub . PMID:19946266 doi:10.1038/nature08624
↑ Rossmann M, Sukumaran M, Penn AC, Veprintsev DB, Babu MM, Greger IH. Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers. EMBO J. 2011 Mar 2;30(5):959-71. Epub 2011 Feb 11. PMID:21317873 doi:10.1038/emboj.2011.16
↑ Ahmed AH, Wang S, Chuang HH, Oswald RE. Mechanism of AMPA receptor activation by partial agonists: disulfide trapping of closed lobe conformations. J Biol Chem. 2011 Aug 16. PMID:21846932 doi:10.1074/jbc.M111.269001
↑ Ahmed AH, Hamada M, Shinada T, Ohfune Y, Weerasinghe L, Garner PP, Oswald RE. The Structure of (-)-Kaitocephalin Bound to the Ligand Binding Domain of the AMPA/Glutamate Receptor, GluA2. J Biol Chem. 2012 Oct 17. PMID:23076153 doi:10.1074/jbc.M112.416362

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4gxs"

Categories: Large Structures | Rattus norvegicus | Ahmed AH | Oswald RE

@@ Line 1: / Line 1: @@
 ==Ligand binding domain of GluA2 (AMPA/glutamate receptor) bound to (-)-kaitocephalin==
-<StructureSection load='4gxs' size='340' side='right' caption='[[4gxs]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
+<StructureSection load='4gxs' size='340' side='right'caption='[[4gxs]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4gxs]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GXS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GXS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4gxs]] is a 2 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=4GXS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GXS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0YS:(5R)-2-[(1S,2R)-2-AMINO-2-CARBOXY-1-HYDROXYETHYL]-5-{(2S)-2-CARBOXY-2-[(3,5-DICHLORO-4-HYDROXYBENZOYL)AMINO]ETHYL}-L-PROLINE'>0YS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9634&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Glur2, Gria2, Gria2; GluA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0YS:(5R)-2-[(1S,2R)-2-AMINO-2-CARBOXY-1-HYDROXYETHYL]-5-{(2S)-2-CARBOXY-2-[(3,5-DICHLORO-4-HYDROXYBENZOYL)AMINO]ETHYL}-L-PROLINE'>0YS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gxs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gxs OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gxs RCSB], [http://www.ebi.ac.uk/pdbsum/4gxs PDBsum]</span></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=4gxs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gxs OCA], [https://pdbe.org/4gxs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gxs RCSB], [https://www.ebi.ac.uk/pdbsum/4gxs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gxs ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4gxs" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Ionotropic Glutamate Receptors|Ionotropic Glutamate Receptors]]
+*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Rattus norvegicus]]
-[[Category: Ahmed, A H]]
+[[Category: Ahmed AH]]
-[[Category: Oswald, R E]]
+[[Category: Oswald RE]]
-[[Category: Ampa receptor]]
-[[Category: Glua2]]
-[[Category: Glur2]]
-[[Category: Glutamate receptor]]
-[[Category: Membrane protein]]
-[[Category: Neurotransmitter receptor]]

4gxs

From Proteopedia

Current revision

Ligand binding domain of GluA2 (AMPA/glutamate receptor) bound to (-)-kaitocephalin

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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