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2xx8

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Revision as of 12:18, 27 April 2022

Crystal structure of N,N-dimethyl-4-(3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1-yl)benzamide in complex with the ligand binding domain of the Rat GluA2 receptor and glutamate at 2.2A resolution.

Structural highlights

2xx8 is a 3 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	1m5c, 1p1o, 1mqh, 1lb8, 1p1u, 1mm7, 1nnp, 1m5d, 1syi, 1p1q, 1mqd, 1mxu, 1my4, 2i3v, 2i3w, 1p1w, 1n0t, 2xxi, 1mqi, 1ftk, 2anj, 1fto, 1my3, 1p1n, 1mxv, 2xx9, 1syh, 1ftj, 1m5e, 1lbb, 1fw0, 1mxz, 1mxy, 1mqg, 2aix, 1m5b, 1mxw, 1ms7, 2xx7, 1my0, 2xxh, 1m5f, 1xhy, 1my1, 2cmo, 1mm6, 2al4, 1mxx, 1ftl, 2uxa, 1wvj, 1ftm, 1lb9, 1lbc, 1nnk, 1my2, 1gr2, 2al5, 1mqj
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

A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.

Integration of Lead Optimization with Crystallography for a Membrane-Bound Ion Channel Target: Discovery of a New Class of AMPA Receptor Positive Allosteric Modulators.,Ward SE, Harries M, Aldegheri L, Austin NE, Ballantine S, Ballini E, Bradley DM, Bax BD, Clarke BP, Harris AJ, Harrison SA, Melarange RA, Mookherjee C, Mosley J, Dal Negro G, Oliosi B, Smith KJ, Thewlis KM, Woollard PM, Yusaf SP J Med Chem. 2010 Dec 3. PMID:21128618^[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
↑ Ward SE, Harries M, Aldegheri L, Austin NE, Ballantine S, Ballini E, Bradley DM, Bax BD, Clarke BP, Harris AJ, Harrison SA, Melarange RA, Mookherjee C, Mosley J, Dal Negro G, Oliosi B, Smith KJ, Thewlis KM, Woollard PM, Yusaf SP. Integration of Lead Optimization with Crystallography for a Membrane-Bound Ion Channel Target: Discovery of a New Class of AMPA Receptor Positive Allosteric Modulators. J Med Chem. 2010 Dec 3. PMID:21128618 doi:10.1021/jm100679e

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/2xx8"

@@ Line 3: / Line 3: @@
 <StructureSection load='2xx8' size='340' side='right'caption='[[2xx8]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2xx8]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XX8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2XX8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2xx8]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XX8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XX8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1NE:N,N-DIMETHYL-4-[3-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDRO-1H-INDAZOL-1-YL]BENZAMIDE'>1NE</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1m5c|1m5c]], [[1p1o|1p1o]], [[1mqh|1mqh]], [[1lb8|1lb8]], [[1p1u|1p1u]], [[1mm7|1mm7]], [[1nnp|1nnp]], [[1m5d|1m5d]], [[1syi|1syi]], [[1p1q|1p1q]], [[1mqd|1mqd]], [[1mxu|1mxu]], [[1my4|1my4]], [[2i3v|2i3v]], [[2i3w|2i3w]], [[1p1w|1p1w]], [[1n0t|1n0t]], [[2xxi|2xxi]], [[1mqi|1mqi]], [[1ftk|1ftk]], [[2anj|2anj]], [[1fto|1fto]], [[1my3|1my3]], [[1p1n|1p1n]], [[1mxv|1mxv]], [[2xx9|2xx9]], [[1syh|1syh]], [[1ftj|1ftj]], [[1m5e|1m5e]], [[1lbb|1lbb]], [[1fw0|1fw0]], [[1mxz|1mxz]], [[1mxy|1mxy]], [[1mqg|1mqg]], [[2aix|2aix]], [[1m5b|1m5b]], [[1mxw|1mxw]], [[1ms7|1ms7]], [[2xx7|2xx7]], [[1my0|1my0]], [[2xxh|2xxh]], [[1m5f|1m5f]], [[1xhy|1xhy]], [[1my1|1my1]], [[2cmo|2cmo]], [[1mm6|1mm6]], [[2al4|2al4]], [[1mxx|1mxx]], [[1ftl|1ftl]], [[2uxa|2uxa]], [[1wvj|1wvj]], [[1ftm|1ftm]], [[1lb9|1lb9]], [[1lbc|1lbc]], [[1nnk|1nnk]], [[1my2|1my2]], [[1gr2|1gr2]], [[2al5|2al5]], [[1mqj|1mqj]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1m5c|1m5c]], [[1p1o|1p1o]], [[1mqh|1mqh]], [[1lb8|1lb8]], [[1p1u|1p1u]], [[1mm7|1mm7]], [[1nnp|1nnp]], [[1m5d|1m5d]], [[1syi|1syi]], [[1p1q|1p1q]], [[1mqd|1mqd]], [[1mxu|1mxu]], [[1my4|1my4]], [[2i3v|2i3v]], [[2i3w|2i3w]], [[1p1w|1p1w]], [[1n0t|1n0t]], [[2xxi|2xxi]], [[1mqi|1mqi]], [[1ftk|1ftk]], [[2anj|2anj]], [[1fto|1fto]], [[1my3|1my3]], [[1p1n|1p1n]], [[1mxv|1mxv]], [[2xx9|2xx9]], [[1syh|1syh]], [[1ftj|1ftj]], [[1m5e|1m5e]], [[1lbb|1lbb]], [[1fw0|1fw0]], [[1mxz|1mxz]], [[1mxy|1mxy]], [[1mqg|1mqg]], [[2aix|2aix]], [[1m5b|1m5b]], [[1mxw|1mxw]], [[1ms7|1ms7]], [[2xx7|2xx7]], [[1my0|1my0]], [[2xxh|2xxh]], [[1m5f|1m5f]], [[1xhy|1xhy]], [[1my1|1my1]], [[2cmo|2cmo]], [[1mm6|1mm6]], [[2al4|2al4]], [[1mxx|1mxx]], [[1ftl|1ftl]], [[2uxa|2uxa]], [[1wvj|1wvj]], [[1ftm|1ftm]], [[1lb9|1lb9]], [[1lbc|1lbc]], [[1nnk|1nnk]], [[1my2|1my2]], [[1gr2|1gr2]], [[2al5|2al5]], [[1mqj|1mqj]]</div></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2xx8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xx8 OCA], [http://pdbe.org/2xx8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xx8 RCSB], [http://www.ebi.ac.uk/pdbsum/2xx8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xx8 ProSAT]</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=2xx8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xx8 OCA], [https://pdbe.org/2xx8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xx8 RCSB], [https://www.ebi.ac.uk/pdbsum/2xx8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xx8 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 ==

2xx8

From Proteopedia

Revision as of 12:18, 27 April 2022

Crystal structure of N,N-dimethyl-4-(3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1-yl)benzamide in complex with the ligand binding domain of the Rat GluA2 receptor and glutamate at 2.2A resolution.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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