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8jd5

From Proteopedia

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Cryo-EM structure of Gi1-bound mGlu2-mGlu4 heterodimer

Structural highlights

8jd5 is a 6 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.6Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GRM2_HUMAN G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.

Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.,Wang X, Wang M, Xu T, Feng Y, Shao Q, Han S, Chu X, Xu Y, Lin S, Zhao Q, Wu B Cell Res. 2023 Jun 8. doi: 10.1038/s41422-023-00830-2. PMID:37286794^[5]

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

References

↑ Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24. PMID:18297054 doi:http://dx.doi.org/10.1038/nature06612
↑ Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M. Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology. 2012 Jun;62(7):2184-91. doi: 10.1016/j.neuropharm.2012.01.010., Epub 2012 Jan 25. PMID:22300836 doi:http://dx.doi.org/10.1016/j.neuropharm.2012.01.010
↑ Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez-Maeso J. Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem. 2012 Dec 28;287(53):44301-19. doi: 10.1074/jbc.M112.413161. Epub, 2012 Nov 5. PMID:23129762 doi:http://dx.doi.org/10.1074/jbc.M112.413161
↑ Flor PJ, Lindauer K, Puttner I, Ruegg D, Lukic S, Knopfel T, Kuhn R. Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2. Eur J Neurosci. 1995 Apr 1;7(4):622-9. PMID:7620613
↑ Wang X, Wang M, Xu T, Feng Y, Shao Q, Han S, Chu X, Xu Y, Lin S, Zhao Q, Wu B. Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers. Cell Res. 2023 Jun 8. PMID:37286794 doi:10.1038/s41422-023-00830-2

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/8jd5"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8jd5]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8JD5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JD5 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BQI:5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine'>BQI</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=HZR:1-butyl-3-chloranyl-4-(4-phenylpiperidin-1-yl)pyridin-2-one'>HZR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEF:DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE'>PEF</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BQI:5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine'>BQI</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=HZR:1-butyl-3-chloranyl-4-(4-phenylpiperidin-1-yl)pyridin-2-one'>HZR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEF:DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE'>PEF</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=8jd5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jd5 OCA], [https://pdbe.org/8jd5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jd5 RCSB], [https://www.ebi.ac.uk/pdbsum/8jd5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jd5 ProSAT]</span></td></tr>
 </table>
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 8jd5" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Metabotropic glutamate receptor 3D structures|Metabotropic glutamate receptor 3D structures]]
+*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
 == References ==
 <references/>

8jd5

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Current revision

Cryo-EM structure of Gi1-bound mGlu2-mGlu4 heterodimer

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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