Cargando…

An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism

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 biologic...

Descripción completa

Detalles Bibliográficos
Autores principales: Lees, Joshua A., Dias, João M., Rajamohan, Francis, Fortin, Jean-Philippe, O’Connor, Rebecca, Kong, Jimmy X., Hughes, Emily A. G., Fisher, Ethan L., Tuttle, Jamison B., Lovett, Gabrielle, Kormos, Bethany L., Unwalla, Rayomand J., Zhang, Lei, Dechert Schmitt, Anne-Marie, Zhou, Dahui, Moran, Michael, Stevens, Kimberly A., Fennell, Kimberly F., Varghese, Alison E., Maxwell, Andrew, Cote, Emmaline E., Zhang, Yuan, Han, Seungil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517971/
https://www.ncbi.nlm.nih.gov/pubmed/37741852
http://dx.doi.org/10.1038/s41467-023-41646-3
_version_ 1785109412072914944
author Lees, Joshua A.
Dias, João M.
Rajamohan, Francis
Fortin, Jean-Philippe
O’Connor, Rebecca
Kong, Jimmy X.
Hughes, Emily A. G.
Fisher, Ethan L.
Tuttle, Jamison B.
Lovett, Gabrielle
Kormos, Bethany L.
Unwalla, Rayomand J.
Zhang, Lei
Dechert Schmitt, Anne-Marie
Zhou, Dahui
Moran, Michael
Stevens, Kimberly A.
Fennell, Kimberly F.
Varghese, Alison E.
Maxwell, Andrew
Cote, Emmaline E.
Zhang, Yuan
Han, Seungil
author_facet Lees, Joshua A.
Dias, João M.
Rajamohan, Francis
Fortin, Jean-Philippe
O’Connor, Rebecca
Kong, Jimmy X.
Hughes, Emily A. G.
Fisher, Ethan L.
Tuttle, Jamison B.
Lovett, Gabrielle
Kormos, Bethany L.
Unwalla, Rayomand J.
Zhang, Lei
Dechert Schmitt, Anne-Marie
Zhou, Dahui
Moran, Michael
Stevens, Kimberly A.
Fennell, Kimberly F.
Varghese, Alison E.
Maxwell, Andrew
Cote, Emmaline E.
Zhang, Yuan
Han, Seungil
author_sort Lees, Joshua A.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10517971
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-105179712023-09-25 An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism Lees, Joshua A. Dias, João M. Rajamohan, Francis Fortin, Jean-Philippe O’Connor, Rebecca Kong, Jimmy X. Hughes, Emily A. G. Fisher, Ethan L. Tuttle, Jamison B. Lovett, Gabrielle Kormos, Bethany L. Unwalla, Rayomand J. Zhang, Lei Dechert Schmitt, Anne-Marie Zhou, Dahui Moran, Michael Stevens, Kimberly A. Fennell, Kimberly F. Varghese, Alison E. Maxwell, Andrew Cote, Emmaline E. Zhang, Yuan Han, Seungil Nat Commun Article 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. Nature Publishing Group UK 2023-09-23 /pmc/articles/PMC10517971/ /pubmed/37741852 http://dx.doi.org/10.1038/s41467-023-41646-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lees, Joshua A.
Dias, João M.
Rajamohan, Francis
Fortin, Jean-Philippe
O’Connor, Rebecca
Kong, Jimmy X.
Hughes, Emily A. G.
Fisher, Ethan L.
Tuttle, Jamison B.
Lovett, Gabrielle
Kormos, Bethany L.
Unwalla, Rayomand J.
Zhang, Lei
Dechert Schmitt, Anne-Marie
Zhou, Dahui
Moran, Michael
Stevens, Kimberly A.
Fennell, Kimberly F.
Varghese, Alison E.
Maxwell, Andrew
Cote, Emmaline E.
Zhang, Yuan
Han, Seungil
An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
title An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
title_full An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
title_fullStr An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
title_full_unstemmed An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
title_short An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
title_sort inverse agonist of orphan receptor gpr61 acts by a g protein-competitive allosteric mechanism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517971/
https://www.ncbi.nlm.nih.gov/pubmed/37741852
http://dx.doi.org/10.1038/s41467-023-41646-3
work_keys_str_mv AT leesjoshuaa aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT diasjoaom aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT rajamohanfrancis aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT fortinjeanphilippe aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT oconnorrebecca aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT kongjimmyx aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT hughesemilyag aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT fisherethanl aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT tuttlejamisonb aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT lovettgabrielle aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT kormosbethanyl aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT unwallarayomandj aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT zhanglei aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT dechertschmittannemarie aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT zhoudahui aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT moranmichael aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT stevenskimberlya aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT fennellkimberlyf aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT varghesealisone aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT maxwellandrew aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT coteemmalinee aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT zhangyuan aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT hanseungil aninverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT leesjoshuaa inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT diasjoaom inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT rajamohanfrancis inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT fortinjeanphilippe inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT oconnorrebecca inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT kongjimmyx inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT hughesemilyag inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT fisherethanl inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT tuttlejamisonb inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT lovettgabrielle inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT kormosbethanyl inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT unwallarayomandj inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT zhanglei inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT dechertschmittannemarie inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT zhoudahui inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT moranmichael inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT stevenskimberlya inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT fennellkimberlyf inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT varghesealisone inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT maxwellandrew inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT coteemmalinee inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT zhangyuan inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism
AT hanseungil inverseagonistoforphanreceptorgpr61actsbyagproteincompetitiveallostericmechanism