8jz7: Difference between revisions
m Protected "8jz7" [edit=sysop:move=sysop] |
No edit summary |
||
| (2 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Cryo-EM structure of MK-6892-bound HCAR2 in complex with Gi protein== | ||
<StructureSection load='8jz7' size='340' side='right'caption='[[8jz7]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8jz7]] 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=8JZ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JZ7 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]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI7:2-[[2,2-dimethyl-3-[3-(5-oxidanylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic+acid'>FI7</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=8jz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jz7 OCA], [https://pdbe.org/8jz7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jz7 RCSB], [https://www.ebi.ac.uk/pdbsum/8jz7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jz7 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_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.<ref>PMID:18611381</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of G(i)-coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 A. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands. | |||
Orthosteric ligand selectivity and allosteric probe dependence at Hydroxycarboxylic acid receptor HCAR2.,Cheng L, Sun S, Wang H, Zhao C, Tian X, Liu Y, Fu P, Shao Z, Chai R, Yan W Signal Transduct Target Ther. 2023 Sep 25;8(1):364. doi: , 10.1038/s41392-023-01625-y. PMID:37743365<ref>PMID:37743365</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8jz7" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Transducin 3D structures|Transducin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Cheng L]] | |||
[[Category: Liu Y]] | |||
[[Category: Shao ZH]] | |||
[[Category: Tian XW]] | |||
[[Category: Yan W]] | |||
[[Category: Zhao C]] | |||
Latest revision as of 17:44, 6 November 2024
Cryo-EM structure of MK-6892-bound HCAR2 in complex with Gi proteinCryo-EM structure of MK-6892-bound HCAR2 in complex with Gi protein
Structural highlights
FunctionGBB1_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.[1] Publication Abstract from PubMedHydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of G(i)-coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 A. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands. Orthosteric ligand selectivity and allosteric probe dependence at Hydroxycarboxylic acid receptor HCAR2.,Cheng L, Sun S, Wang H, Zhao C, Tian X, Liu Y, Fu P, Shao Z, Chai R, Yan W Signal Transduct Target Ther. 2023 Sep 25;8(1):364. doi: , 10.1038/s41392-023-01625-y. PMID:37743365[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||