+検索条件
-Structure paper
タイトル | An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism. |
---|---|
ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 5938, Year 2023 |
掲載日 | 2023年9月23日 |
著者 | Joshua A Lees / João M Dias / Francis Rajamohan / Jean-Philippe Fortin / Rebecca O'Connor / Jimmy X Kong / Emily A G Hughes / Ethan L Fisher / Jamison B Tuttle / Gabrielle Lovett / Bethany L Kormos / Rayomand J Unwalla / Lei Zhang / Anne-Marie Dechert Schmitt / Dahui Zhou / Michael Moran / Kimberly A Stevens / Kimberly F Fennell / Alison E Varghese / Andrew Maxwell / Emmaline E Cote / Yuan Zhang / Seungil Han / |
PubMed 要旨 | GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body ...GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation. |
リンク | Nat Commun / PubMed:37741852 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.94 - 3.47 Å |
構造データ | EMDB-41144, PDB-8tb0: EMDB-41145, PDB-8tb7: |
化合物 | ChemComp-ZOB: ChemComp-HOH: |
由来 |
|
キーワード | SIGNALING PROTEIN / GPR61 / GPCR (Gタンパク質共役受容体) / Signaling complex / inverse agonist (受容体逆作動薬) / membrane protein (膜タンパク質) / BRIL |