May 14 – 19, 2023
Hotel Hermitage, La Biodola Bay, Elba Island, Italy
Europe/Rome timezone

Selecting Synthetic Photoswitches for Time-Resolved Serial Crystallography of the Human A2A Receptor

May 17, 2023, 4:15 PM
Hotel Hermitage, La Biodola Bay, Elba Island, Italy

Hotel Hermitage, La Biodola Bay, Elba Island, Italy

Biodola Bay 57037 Portoferraio (LI) Isola d’Elba - Italy


Hannah Glover (Paul Scherrer Institut)


Time-resolved serial crystallography has emerged as a method to study protein dynamics at atomic resolution. In this method, reactions need to be initiated synchronously. Many experiments have used light as a trigger system to study endogenously photoactive proteins; however, only a small fraction of proteins are naturally photoactive. Therefore, work needs to be done to ensure this method can be applied to a wider range of pharmacologically relevant proteins. Synthetic photoswitches have been developed through the field of photopharmacology that convert between binding and nonbinding conformations. Here we present the characterisation of eight synthetic photoswitches, derived from an approved treatment against Parkinson’s disease. We observed that photoisomerisation properties can differ in crystallo from in solution, indicating that not all photoswitches are suitable for time-resolved crystallography. We applied synthetic photoswitches to observe the process of ligand dissociation from the human A2A receptor, a G protein-coupled receptor. An understanding of this process can help guide the development of drugs with increased residence times. Using data collected at SLS, MaxIV and the SwissFEL, we follow how the binding pocket adapts to accommodate ligands and movement in the hydrogen-bonded lid of the binding pocket during ligand dissociation.

Select Topic 1 Modern Methods in Structural Biology and Dynamics
Select Topic 2 Drug Discovery

Primary author

Hannah Glover (Paul Scherrer Institut)


Dr Matilde Trabuco (leadXproo) Robin Stipp Mr Torben Saßmannshausen (University of Frankfurt) Prof. Michael Hennig (leadXpro) Prof. Josef Wachtveitl (University of Frankfurt) Joerg Standfuss (Paul Scherrer Institut)

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