Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography

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 and Joerg Standfuss ()
Additional contact information
Hannah Glover: PSI Center for Life Sciences
Torben Saßmannshausen: Goethe University
Quentin Bertrand: PSI Center for Life Sciences
Matilde Trabuco: Park Innovaare
Chavdar Slavov: Goethe University
Arianna Bacchin: Park Innovaare
Fabio Andres: Park Innovaare
Yasushi Kondo: PSI Center for Life Sciences
Robin Stipp: PSI Center for Life Sciences
Maximilian Wranik: PSI Center for Life Sciences
Georgii Khusainov: PSI Center for Life Sciences
Melissa Carrillo: PSI Center for Life Sciences
Demet Kekilli: PSI Center for Life Sciences
Jie Nan: Lund University
Ana Gonzalez: Lund University
Robert Cheng: Park Innovaare
Werner Neidhart: Park Innovaare
Tobias Weinert: PSI Center for Life Sciences
Filip Leonarski: PSI Center for Photon Sciences
Florian Dworkowski: PSI Center for Photon Sciences
Michal Kepa: PSI Center for Life Sciences
Josef Wachtveitl: Goethe University
Michael Hennig: Park Innovaare
Joerg Standfuss: PSI Center for Life Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-55109-w

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