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5mfv

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Crystal structure of the GluK1 ligand-binding domain in complex with kainate and BPAM-521 at 2.18 A resolution

Structural highlights

5mfv 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 2.181Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GRIK1_RAT Ionotropic glutamate receptor. 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. May be involved in the transmission of light information from the retina to the hypothalamus.^[1]

Publication Abstract from PubMed

Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of AMPA receptors have been reported, no such ligands are available for KARs. In this study, we have investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. BPAM344 potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 muM), with an EC50 of 79 muM. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. BPAM521 potentiated the recorded peak current amplitude of GluK2a 12-fold at a concentration of 300 muM with an EC50 value of 159 muM, whereas no potentiation of the glutamate-evoked response was observed for BPAM121 at the highest concentration of modulator tested (300 muM). BPAM344 (100 muM) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15-fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1i (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator-binding sites at the GluK1 dimer interface. In conclusion, this study opens for the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigating the function of KARs in vivo and may prove useful to phamacologically control the activity of neuronal networks.

Identification and structure-function study of positive allosteric modulators of kainate receptors.,Larsen AP, Fievre S, Frydenvang K, Francotte P, Pirotte B, Karstrup JS, Mulle C Mol Pharmacol. 2017 Mar 30. pii: mol.116.107599. doi: 10.1124/mol.116.107599. PMID:28360094^[2]

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

References

↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
↑ Larsen AP, Fievre S, Frydenvang K, Francotte P, Pirotte B, Karstrup JS, Mulle C. Identification and structure-function study of positive allosteric modulators of kainate receptors. Mol Pharmacol. 2017 Mar 30. pii: mol.116.107599. doi: 10.1124/mol.116.107599. PMID:28360094 doi:http://dx.doi.org/10.1124/mol.116.107599

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/5mfv"

Categories: Large Structures | Rattus norvegicus | Frydenvang K | Kastrup JS | Larsen AP

@@ Line 1: / Line 1: @@
 ==Crystal structure of the GluK1 ligand-binding domain in complex with kainate and BPAM-521 at 2.18 A resolution==
-<StructureSection load='5mfv' size='340' side='right' caption='[[5mfv]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
+<StructureSection load='5mfv' size='340' side='right'caption='[[5mfv]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mfv]] is a 2 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=5MFV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MFV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mfv]] 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=5MFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MFV FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5PX:4-CYCLOPROPYL-3,4-DIHYDRO-7-HYDROXY-2H-1,2,4-BENZOTHIADIAZINE+1,1-DIOXIDE'>5PX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KAI:3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE'>KAI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.181&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Grik1, Glur5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5PX:4-CYCLOPROPYL-3,4-DIHYDRO-7-HYDROXY-2H-1,2,4-BENZOTHIADIAZINE+1,1-DIOXIDE'>5PX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KAI:3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE'>KAI</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mfv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mfv OCA], [http://pdbe.org/5mfv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mfv RCSB], [http://www.ebi.ac.uk/pdbsum/5mfv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mfv 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=5mfv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mfv OCA], [https://pdbe.org/5mfv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mfv RCSB], [https://www.ebi.ac.uk/pdbsum/5mfv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mfv ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GRIK1_RAT GRIK1_RAT]] Ionotropic glutamate receptor. 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. May be involved in the transmission of light information from the retina to the hypothalamus.<ref>PMID:16540562</ref>
+[https://www.uniprot.org/uniprot/GRIK1_RAT GRIK1_RAT] Ionotropic glutamate receptor. 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. May be involved in the transmission of light information from the retina to the hypothalamus.<ref>PMID:16540562</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5mfv" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Buffalo rat]]
+[[Category: Large Structures]]
-[[Category: Frydenvang, K]]
+[[Category: Rattus norvegicus]]
-[[Category: Kastrup, J S]]
+[[Category: Frydenvang K]]
-[[Category: Larsen, A P]]
+[[Category: Kastrup JS]]
-[[Category: Gluk1 ligand-binding domain]]
+[[Category: Larsen AP]]
-[[Category: Ionotropic glutamate receptor]]
-[[Category: Membrane protein]]
-[[Category: Positive allosteric modulator]]

5mfv

From Proteopedia

Current revision

Crystal structure of the GluK1 ligand-binding domain in complex with kainate and BPAM-521 at 2.18 A resolution

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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