Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography
Abstract G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve p...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55109-w |
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| author | Hannah Glover Torben Saßmannshausen Quentin Bertrand Matilde Trabuco Chavdar Slavov Arianna Bacchin Fabio Andres Yasushi Kondo Robin Stipp Maximilian Wranik Georgii Khusainov Melissa Carrillo Demet Kekilli Jie Nan Ana Gonzalez Robert Cheng Werner Neidhart Tobias Weinert Filip Leonarski Florian Dworkowski Michal Kepa Josef Wachtveitl Michael Hennig Joerg Standfuss |
| author_facet | Hannah Glover Torben Saßmannshausen Quentin Bertrand Matilde Trabuco Chavdar Slavov Arianna Bacchin Fabio Andres Yasushi Kondo Robin Stipp Maximilian Wranik Georgii Khusainov Melissa Carrillo Demet Kekilli Jie Nan Ana Gonzalez Robert Cheng Werner Neidhart Tobias Weinert Filip Leonarski Florian Dworkowski Michal Kepa Josef Wachtveitl Michael Hennig Joerg Standfuss |
| author_sort | Hannah Glover |
| collection | DOAJ |
| description | Abstract G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A2A receptor. For this, we designed seven photochemical affinity switches derived from the anti-Parkinson’s drug istradefylline. In a rational approach based on UV/Vis spectroscopy, time-resolved absorption spectroscopy, differential scanning fluorimetry and cryo-crystallography, we identified compounds suitable for time-resolved serial crystallography. Our analysis of millisecond-scale dynamics revealed how trans-to-cis isomerization shifts selected istradefylline derivatives within the binding pocket. Depending on the chemical nature of the ligand, interactions between extracellular loops 2 and 3, acting as a lid on the binding pocket, are disrupted and rearrangement of the orthosteric binding pocket is invoked upon ligand dissociation. This innovative approach provides insights into GPCR dynamics at the atomic level, offering potential for developing novel pharmaceuticals. |
| format | Article |
| id | doaj-art-ab3f8563ff254f398b3e8a54f3a1a6df |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ab3f8563ff254f398b3e8a54f3a1a6df2025-01-05T12:35:57ZengNature PortfolioNature Communications2041-17232024-12-0115111310.1038/s41467-024-55109-wPhotoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallographyHannah Glover0Torben Saßmannshausen1Quentin Bertrand2Matilde Trabuco3Chavdar Slavov4Arianna Bacchin5Fabio Andres6Yasushi Kondo7Robin Stipp8Maximilian Wranik9Georgii Khusainov10Melissa Carrillo11Demet Kekilli12Jie Nan13Ana Gonzalez14Robert Cheng15Werner Neidhart16Tobias Weinert17Filip Leonarski18Florian Dworkowski19Michal Kepa20Josef Wachtveitl21Michael Hennig22Joerg Standfuss23PSI Center for Life SciencesInstitute of Physical and Theoretical Chemistry, Goethe UniversityPSI Center for Life SciencesleadXpro AG, Park InnovaareInstitute of Physical and Theoretical Chemistry, Goethe UniversityleadXpro AG, Park InnovaareleadXpro AG, Park InnovaarePSI Center for Life SciencesPSI Center for Life SciencesPSI Center for Life SciencesPSI Center for Life SciencesPSI Center for Life SciencesPSI Center for Life SciencesMaxIV Laboratory, Lund UniversityMaxIV Laboratory, Lund UniversityleadXpro AG, Park InnovaareleadXpro AG, Park InnovaarePSI Center for Life SciencesPSI Center for Photon SciencesPSI Center for Photon SciencesPSI Center for Life SciencesInstitute of Physical and Theoretical Chemistry, Goethe UniversityleadXpro AG, Park InnovaarePSI Center for Life SciencesAbstract G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A2A receptor. For this, we designed seven photochemical affinity switches derived from the anti-Parkinson’s drug istradefylline. In a rational approach based on UV/Vis spectroscopy, time-resolved absorption spectroscopy, differential scanning fluorimetry and cryo-crystallography, we identified compounds suitable for time-resolved serial crystallography. Our analysis of millisecond-scale dynamics revealed how trans-to-cis isomerization shifts selected istradefylline derivatives within the binding pocket. Depending on the chemical nature of the ligand, interactions between extracellular loops 2 and 3, acting as a lid on the binding pocket, are disrupted and rearrangement of the orthosteric binding pocket is invoked upon ligand dissociation. This innovative approach provides insights into GPCR dynamics at the atomic level, offering potential for developing novel pharmaceuticals.https://doi.org/10.1038/s41467-024-55109-w |
| spellingShingle | Hannah Glover Torben Saßmannshausen Quentin Bertrand Matilde Trabuco Chavdar Slavov Arianna Bacchin Fabio Andres Yasushi Kondo Robin Stipp Maximilian Wranik Georgii Khusainov Melissa Carrillo Demet Kekilli Jie Nan Ana Gonzalez Robert Cheng Werner Neidhart Tobias Weinert Filip Leonarski Florian Dworkowski Michal Kepa Josef Wachtveitl Michael Hennig Joerg Standfuss Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography Nature Communications |
| title | Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography |
| title_full | Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography |
| title_fullStr | Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography |
| title_full_unstemmed | Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography |
| title_short | Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography |
| title_sort | photoswitch dissociation from a g protein coupled receptor resolved by time resolved serial crystallography |
| url | https://doi.org/10.1038/s41467-024-55109-w |
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