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| | <StructureSection load='6li0' size='340' side='right'caption='[[6li0]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='6li0' size='340' side='right'caption='[[6li0]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6li0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Desvh Desvh]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LI0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6LI0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6li0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Desulfovibrio_vulgaris_str._Hildenborough Desulfovibrio vulgaris str. Hildenborough] 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=6LI0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LI0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EN6:N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide'>EN6</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GPR52 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=882 DESVH])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EN6:N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide'>EN6</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=6li0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6li0 OCA], [http://pdbe.org/6li0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6li0 RCSB], [http://www.ebi.ac.uk/pdbsum/6li0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6li0 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=6li0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6li0 OCA], [https://pdbe.org/6li0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6li0 RCSB], [https://www.ebi.ac.uk/pdbsum/6li0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6li0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GPR52_HUMAN GPR52_HUMAN]] Gs-coupled receptor activated by antipsychotics reserpine leading to an increase in intracellular cAMP and its internalization (PubMed:24587241). May play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. These behavioral changes are accompanied by modulation of the dopamine receptor signaling pathway in striatum (PubMed:24587241). Modulates HTT level via cAMP-dependent but PKA independent mechanisms throught activation of RAB39B that translocates HTT to the endoplasmic reticulum, thus avoiding proteasome degradation (PubMed:25738228).<ref>PMID:24587241</ref> <ref>PMID:25738228</ref> | + | [https://www.uniprot.org/uniprot/FLAV_DESVH FLAV_DESVH] Low-potential electron donor to a number of redox enzymes.[https://www.uniprot.org/uniprot/GPR52_HUMAN GPR52_HUMAN] Gs-coupled receptor activated by antipsychotics reserpine leading to an increase in intracellular cAMP and its internalization (PubMed:24587241). May play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. These behavioral changes are accompanied by modulation of the dopamine receptor signaling pathway in striatum (PubMed:24587241). Modulates HTT level via cAMP-dependent but PKA independent mechanisms throught activation of RAB39B that translocates HTT to the endoplasmic reticulum, thus avoiding proteasome degradation (PubMed:25738228).<ref>PMID:24587241</ref> <ref>PMID:25738228</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders(1,2). Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric Gs protein(2), but it is unclear how GPR52 and Gs couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a Gs-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52(3). A fully active state is achieved when Gs is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.
| + | |
| - | | + | |
| - | Structural basis of ligand recognition and self-activation of orphan GPR52.,Lin X, Li M, Wang N, Wu Y, Luo Z, Guo S, Han GW, Li S, Yue Y, Wei X, Xie X, Chen Y, Zhao S, Wu J, Lei M, Xu F Nature. 2020 Feb 19. pii: 10.1038/s41586-020-2019-0. doi:, 10.1038/s41586-020-2019-0. PMID:32076264<ref>PMID:32076264</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6li0" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Desvh]] | + | [[Category: Desulfovibrio vulgaris str. Hildenborough]] |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Han, G W]] | + | [[Category: Han GW]] |
| - | [[Category: Lin, X]] | + | [[Category: Lin X]] |
| - | [[Category: Luo, Z P]] | + | [[Category: Luo ZP]] |
| - | [[Category: Xu, F]] | + | [[Category: Xu F]] |
| - | [[Category: Agonist c17]]
| + | |
| - | [[Category: Class some]]
| + | |
| - | [[Category: Flavodoxin]]
| + | |
| - | [[Category: Human gpr52 receptor]]
| + | |
| - | [[Category: Lcp]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Orphan gpcr]]
| + | |
| Structural highlights
6li0 is a 1 chain structure with sequence from Desulfovibrio vulgaris str. Hildenborough and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.2Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
FLAV_DESVH Low-potential electron donor to a number of redox enzymes.GPR52_HUMAN Gs-coupled receptor activated by antipsychotics reserpine leading to an increase in intracellular cAMP and its internalization (PubMed:24587241). May play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. These behavioral changes are accompanied by modulation of the dopamine receptor signaling pathway in striatum (PubMed:24587241). Modulates HTT level via cAMP-dependent but PKA independent mechanisms throught activation of RAB39B that translocates HTT to the endoplasmic reticulum, thus avoiding proteasome degradation (PubMed:25738228).[1] [2]
References
- ↑ Komatsu H, Maruyama M, Yao S, Shinohara T, Sakuma K, Imaichi S, Chikatsu T, Kuniyeda K, Siu FK, Peng LS, Zhuo K, Mun LS, Han TM, Matsumoto Y, Hashimoto T, Miyajima N, Itoh Y, Ogi K, Habata Y, Mori M. Anatomical transcriptome of G protein-coupled receptors leads to the identification of a novel therapeutic candidate GPR52 for psychiatric disorders. PLoS One. 2014 Feb 28;9(2):e90134. doi: 10.1371/journal.pone.0090134. eCollection, 2014. PMID:24587241 doi:http://dx.doi.org/10.1371/journal.pone.0090134
- ↑ Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J, Difiglia M, Palacino J, Wu ZY, Ma L, Botas J, Lu B. A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. Elife. 2015 Mar 4;4. doi: 10.7554/eLife.05449. PMID:25738228 doi:http://dx.doi.org/10.7554/eLife.05449
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