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LEAPS Meets Life Sciences Conference

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

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Watching the release of a photopharmacological drug from its target using SLS and SwissFEL

17 May 2023, 19:45
30m
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

Speaker

Jörg Standfuss (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland)

Description

Photopharmacology offers a powerful approach to alter ligand affinity and biological activity of small molecule drugs using light as a trigger. However, understanding the molecular mechanisms underlying this process has been challenging due to the inability of conventional structural biology to resolve the relevant transitions. In this presentation, I will outline how we employed time-resolved serial crystallography at the Swiss Light Source (SLS) and the Swiss X-ray Free Electron Laser (SwissFEL) to capture the release of azo-combretastatin A4, an anti-cancer compound, and the resulting conformational changes in tubulin. We obtained a series of structural snapshots logarithmically spaced in time from 100 fs to 100 ms, which, along with computer simulations and time-resolved spectroscopy, provide direct molecular insight into how the cis-to-trans isomerization of the azobenzene bond leads to a switch in ligand affinity, opening of an exit channel, and collapse of the binding pocket upon ligand release. The resulting global backbone rearrangements are related to the action mechanism of microtubule-destabilizing drugs.

References
[1] M. Wranik et al., Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography. Nat Commun 14, 903 (2023).

Select Topic 1 Drug Discovery

Primary author

Jörg Standfuss (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland)

Co-authors

Andrea Cavalli (Computational and Chemical Biology, Instituto Italiano die Tecnologia, 16163 Genova, Italy) Antonia Furrer (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Camila Bacellar (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Chavdar Slavov (Institute of Physical and Theoretical Chemistry, Goethe University, Frankfurt am Main, Germany) Chris Milne (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Claudio Cirelli (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Daniel James (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Dardan Gashi (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Dario Gioia (Computational and Chemical Biology, Instituto Italiano die Tecnologia, 16163 Genova, Italy) Demet Kekilli (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Dmitry Ozerov (Scientific Computing, Theory and Data, Paul Scherrer Institut, 5232 Villigen, Switzerland) Florian Dworkowski (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Hannah Glover (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) John Beale (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Josef Wachtveitl (Institute of Physical and Theoretical Chemistry, Goethe University, Frankfurt am Main, Germany) Karol Nass (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Marco Ferrarotti (Computational and Chemical Biology, Instituto Italiano die Tecnologia, 16163 Genova, Italy) Markus Braun (Institute of Physical and Theoretical Chemistry, Goethe University, Frankfurt am Main, Germany) Maximilian Wranik (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Meitian Wang (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Melissa Carrillo (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Michel Steinmetz (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Natacha Gaillard (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Petr Skopintsev (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Philip J.M. Johnson (Photon Science Division, Paul Scherrer Institut, 5232 Villigen, Switzerland) Robin Stipp (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Steffen Brünle (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Tiziana Masini (Computational and Chemical Biology, Instituto Italiano die Tecnologia, 16163 Genova, Italy) Tobias Mühlethaler (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland) Tobias Weinert (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland)

Presentation materials

2305-LEAPSmeetsLifeSciences-StandfussShare.pdf
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