8jhy
From Proteopedia
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<table><tr><td colspan='2'>[[8jhy]] is a 5 chain structure with sequence from [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=8JHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JHY FirstGlance]. <br> | <table><tr><td colspan='2'>[[8jhy]] is a 5 chain structure with sequence from [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=8JHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JHY 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]] 2.87Å</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]] 2.87Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=IX8:7-methyl-N-[( | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=IX8:7-methyl-~{N}-[(2~{R})-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide'>IX8</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=8jhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jhy OCA], [https://pdbe.org/8jhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jhy RCSB], [https://www.ebi.ac.uk/pdbsum/8jhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jhy 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=8jhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jhy OCA], [https://pdbe.org/8jhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jhy RCSB], [https://www.ebi.ac.uk/pdbsum/8jhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jhy ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| - | [https://www.uniprot.org/uniprot/ | + | [https://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). |
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body beta-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G(i/o) protein or beta-arrestin effectors. Here, we characterize compound 9n as a G(i)-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G(i) pathway. Furthermore, four structures of HCAR2-G(i) complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs. | Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body beta-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G(i/o) protein or beta-arrestin effectors. Here, we characterize compound 9n as a G(i)-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G(i) pathway. Furthermore, four structures of HCAR2-G(i) complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs. | ||
| - | Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.,Zhao C, Wang H, Liu Y, Cheng L, Wang B, Tian X, Fu H, Wu C, Li Z, Shen C, Yu J, Yang S, Hu H, Fu P, Ma L, Wang C, Yan W, Shao Z Mol Cell. 2023 | + | Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.,Zhao C, Wang H, Liu Y, Cheng L, Wang B, Tian X, Fu H, Wu C, Li Z, Shen C, Yu J, Yang S, Hu H, Fu P, Ma L, Wang C, Yan W, Shao Z Mol Cell. 2023 Sep 7;83(17):3171-3187.e7. doi: 10.1016/j.molcel.2023.07.030. Epub , 2023 Aug 18. PMID:37597514<ref>PMID:37597514</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8jhy" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8jhy" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Transducin 3D structures|Transducin 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Cryo-EM structure of compound 9n bound ketone body receptor HCAR2-Gi signaling complex
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Categories: Homo sapiens | Large Structures | Mus musculus | Cheng L | Liu Y | Shao ZH | Tian XW | Yan W | Zhao C
