8hvi: Difference between revisions
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==Activation mechanism of GPR132 by compound NOX-6-7== | |||
<StructureSection load='8hvi' size='340' side='right'caption='[[8hvi]], [[Resolution|resolution]] 3.04Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8hvi]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HVI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HVI FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.04Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NFI:3-methyl-5-[(4-oxidanylidene-4-phenyl-butanoyl)amino]-1-benzofuran-2-carboxylic+acid'>NFI</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=8hvi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hvi OCA], [https://pdbe.org/8hvi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hvi RCSB], [https://www.ebi.ac.uk/pdbsum/8hvi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hvi ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GP132_HUMAN GP132_HUMAN] May be a receptor for oxidized free fatty acids derived from linoleic and arachidonic acids such as 9-hydroxyoctadecadienoic acid (9-HODE). Activates a G alpha protein, most likely G alpha(q). May be involved in apoptosis. Functions at the G2/M checkpoint to delay mitosis. May function as a sensor that monitors the oxidative states and mediates appropriate cellular responses such as secretion of paracrine signals and attenuation of proliferation. May mediate ths accumulation of intracellular inositol phosphates at acidic pH through proton-sensing activity.<ref>PMID:12586833</ref> <ref>PMID:19855098</ref> <ref>PMID:9770487</ref> [https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes. | |||
Functional screening and rational design of compounds targeting GPR132 to treat diabetes.,Wang JL, Dou XD, Cheng J, Gao MX, Xu GF, Ding W, Ding JH, Li Y, Wang SH, Ji ZW, Zhao XY, Huo TY, Zhang CF, Liu YM, Sha XY, Gao JR, Zhang WH, Hao Y, Zhang C, Sun JP, Jiao N, Yu X Nat Metab. 2023 Sep 28. doi: 10.1038/s42255-023-00899-4. PMID:37770763<ref>PMID:37770763</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8hvi" style="background-color:#fffaf0;"></div> | ||
[[Category: Ding | == References == | ||
[[Category: Sun | <references/> | ||
[[Category: Wang | __TOC__ | ||
</StructureSection> | |||
[[Category: Escherichia coli]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Ding JH]] | |||
[[Category: Sun JP]] | |||
[[Category: Wang JL]] | |||
[[Category: Yu X]] | |||
Revision as of 08:58, 11 October 2023
Activation mechanism of GPR132 by compound NOX-6-7Activation mechanism of GPR132 by compound NOX-6-7
Structural highlights
FunctionGP132_HUMAN May be a receptor for oxidized free fatty acids derived from linoleic and arachidonic acids such as 9-hydroxyoctadecadienoic acid (9-HODE). Activates a G alpha protein, most likely G alpha(q). May be involved in apoptosis. Functions at the G2/M checkpoint to delay mitosis. May function as a sensor that monitors the oxidative states and mediates appropriate cellular responses such as secretion of paracrine signals and attenuation of proliferation. May mediate ths accumulation of intracellular inositol phosphates at acidic pH through proton-sensing activity.[1] [2] [3] C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedChronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes. Functional screening and rational design of compounds targeting GPR132 to treat diabetes.,Wang JL, Dou XD, Cheng J, Gao MX, Xu GF, Ding W, Ding JH, Li Y, Wang SH, Ji ZW, Zhao XY, Huo TY, Zhang CF, Liu YM, Sha XY, Gao JR, Zhang WH, Hao Y, Zhang C, Sun JP, Jiao N, Yu X Nat Metab. 2023 Sep 28. doi: 10.1038/s42255-023-00899-4. PMID:37770763[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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