6li2

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of GPR52 ligand free form with rubredoxin fusion

Structural highlights

6li2 is a 1 chain structure with sequence from Clostridium pasteurianum 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 2.8Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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] RUBR_CLOPA Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule.

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^[3]

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

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
↑ 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. Structural basis of ligand recognition and self-activation of orphan GPR52. Nature. 2020 Feb 19. pii: 10.1038/s41586-020-2019-0. doi:, 10.1038/s41586-020-2019-0. PMID:32076264 doi:http://dx.doi.org/10.1038/s41586-020-2019-0

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6li2"

@@ Line 3: / Line 3: @@
 <StructureSection load='6li2' size='340' side='right'caption='[[6li2]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6li2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pasteurianus"_(winogradsky_1895)_lehmann_and_neumann_1907 "bacillus pasteurianus" (winogradsky 1895) lehmann and neumann 1907]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LI2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6LI2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6li2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_pasteurianum Clostridium pasteurianum] 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=6LI2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LI2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.8&#8491;</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=1501 "Bacillus pasteurianus" (Winogradsky 1895) Lehmann and Neumann 1907])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=6li2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6li2 OCA], [http://pdbe.org/6li2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6li2 RCSB], [http://www.ebi.ac.uk/pdbsum/6li2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6li2 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=6li2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6li2 OCA], [https://pdbe.org/6li2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6li2 RCSB], [https://www.ebi.ac.uk/pdbsum/6li2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6li2 ProSAT]</span></td></tr>
 </table>
 == 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/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/RUBR_CLOPA RUBR_CLOPA] Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Clostridium pasteurianum]]
+[[Category: Homo sapiens]]
 [[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: Apo form]]
-[[Category: Class some]]
-[[Category: Human gpr52 receptor]]
-[[Category: Lcp]]
-[[Category: Membrane protein]]
-[[Category: Orphan gpcr]]
-[[Category: Rubredoxin]]

6li2

From Proteopedia

Current revision

Crystal structure of GPR52 ligand free form with rubredoxin fusion

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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