Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography
(2024) In Nature Communications 15(1).- 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... (More)
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.
(Less)
- author
- Glover, Hannah
; Saßmannshausen, Torben
; Bertrand, Quentin
; Trabuco, Matilde
; Slavov, Chavdar
; Bacchin, Arianna
; Andres, Fabio
; Kondo, Yasushi
; Stipp, Robin
; Wranik, Maximilian
; Khusainov, Georgii
; Carrillo, Melissa
; Kekilli, Demet
; Nan, Jie
LU
; Gonzalez, Ana
LU
; Cheng, Robert
; Neidhart, Werner
; Weinert, Tobias
; Leonarski, Filip
; Dworkowski, Florian
; Kepa, Michal
LU
; Wachtveitl, Josef
; Hennig, Michael
and Standfuss, Joerg
(Less) - organization
- publishing date
- 2024-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 15
- issue
- 1
- article number
- 10837
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:39738009
- scopus:85213733192
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-024-55109-w
- language
- English
- LU publication?
- yes
- id
- 18edaa2b-5a35-41a1-91d5-ebde10370878
- date added to LUP
- 2025-02-24 16:41:20
- date last changed
- 2025-07-01 12:40:38
@article{18edaa2b-5a35-41a1-91d5-ebde10370878,
abstract = {{<p>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 A<sub>2A</sub> 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.</p>}},
author = {{Glover, Hannah and Saßmannshausen, Torben and Bertrand, Quentin and Trabuco, Matilde and Slavov, Chavdar and Bacchin, Arianna and Andres, Fabio and Kondo, Yasushi and Stipp, Robin and Wranik, Maximilian and Khusainov, Georgii and Carrillo, Melissa and Kekilli, Demet and Nan, Jie and Gonzalez, Ana and Cheng, Robert and Neidhart, Werner and Weinert, Tobias and Leonarski, Filip and Dworkowski, Florian and Kepa, Michal and Wachtveitl, Josef and Hennig, Michael and Standfuss, Joerg}},
issn = {{2041-1723}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography}},
url = {{http://dx.doi.org/10.1038/s41467-024-55109-w}},
doi = {{10.1038/s41467-024-55109-w}},
volume = {{15}},
year = {{2024}},
}