A non-canonical mechanism of GPCR activation
Abstract The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepte...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54103-6 |
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| author | Alexander S. Powers Aasma Khan Joseph M. Paggi Naomi R. Latorraca Sarah Souza Jerry Di Salvo Jun Lu Stephen M. Soisson Jennifer M. Johnston Adam B. Weinglass Ron O. Dror |
| author_facet | Alexander S. Powers Aasma Khan Joseph M. Paggi Naomi R. Latorraca Sarah Souza Jerry Di Salvo Jun Lu Stephen M. Soisson Jennifer M. Johnston Adam B. Weinglass Ron O. Dror |
| author_sort | Alexander S. Powers |
| collection | DOAJ |
| description | Abstract The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists—ligands that trigger GPCR activation—function by causing rearrangement of the GPCR’s transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers. We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations that disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate the signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets. |
| format | Article |
| id | doaj-art-4b97ff53806049ee92388f4ef8a727d4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4b97ff53806049ee92388f4ef8a727d42024-11-17T12:36:27ZengNature PortfolioNature Communications2041-17232024-11-0115111210.1038/s41467-024-54103-6A non-canonical mechanism of GPCR activationAlexander S. Powers0Aasma Khan1Joseph M. Paggi2Naomi R. Latorraca3Sarah Souza4Jerry Di Salvo5Jun Lu6Stephen M. Soisson7Jennifer M. Johnston8Adam B. Weinglass9Ron O. Dror10Department of Chemistry, Stanford UniversityDepartment of Quantitative Biosciences, Merck & Co., Inc.Department of Computer Science, Stanford UniversityDepartment of Computer Science, Stanford UniversityDepartment of Quantitative Biosciences, Merck & Co., Inc.EvotecDepartment of Structural Chemistry, Merck & Co., Inc.Department of Structural Chemistry, Merck & Co., Inc.Department of Modeling and Informatics, Merck & Co., Inc.Department of Quantitative Biosciences, Merck & Co., Inc.Department of Computer Science, Stanford UniversityAbstract The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists—ligands that trigger GPCR activation—function by causing rearrangement of the GPCR’s transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers. We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations that disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate the signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets.https://doi.org/10.1038/s41467-024-54103-6 |
| spellingShingle | Alexander S. Powers Aasma Khan Joseph M. Paggi Naomi R. Latorraca Sarah Souza Jerry Di Salvo Jun Lu Stephen M. Soisson Jennifer M. Johnston Adam B. Weinglass Ron O. Dror A non-canonical mechanism of GPCR activation Nature Communications |
| title | A non-canonical mechanism of GPCR activation |
| title_full | A non-canonical mechanism of GPCR activation |
| title_fullStr | A non-canonical mechanism of GPCR activation |
| title_full_unstemmed | A non-canonical mechanism of GPCR activation |
| title_short | A non-canonical mechanism of GPCR activation |
| title_sort | non canonical mechanism of gpcr activation |
| url | https://doi.org/10.1038/s41467-024-54103-6 |
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