GRK 2905 – Ultrafast Nanoscopy
From single particle dynamics to cooperative processes
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Colloquium:
Photopharmacology Across Time and Space: Molecular Insights via X-ray Free Electron Lasers
November 8 @ 15:00 – 16:00
RUN auditorium
Dr. Jörg Standfuss
Lab. for Biomolecular Research, PSI Center for Life Sciences, Switzerland
Structural biology has been critical for our understanding of how proteins work on the molecular level. However, resolving the temporal evolution of biological macromolecules in response to activating stimuli—such as the binding of small molecular ligands or drug molecules—remains a challenge. In recent years, our research group has leveraged X-ray Free Electron Laser facilities to experimentally investigate how retinal-binding rhodopsins, acting as pumps, channels, or light sensors, are activated at the atomic level across a wide range of time scales.
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In our latest experiments at the Swiss X-ray Free Electron Laser, we explored how photoactive azobenzene compounds, mimicking retinal, can be used to trigger protein dynamics for structural studies. My presentation will focus on the dissociation dynamics of the photopharmacological drug candidate azo-combretastatin A4 from tubulin, capturing events from the initial photochemical reaction in the femtosecond range, through the disruption of high-affinity protein-ligand interactions in nanoseconds, adaptation of the binding pocket in microseconds, and the eventual release of the compound in milliseconds. I will discuss the relevance of these findings for our understanding of how anti-cancer drugs destabilize the microtubule network. Furthermore, I will propose the use of azobenzene-based photoswitches to trigger G protein-coupled receptors and other pharmacologically relevant targets in time-resolved structural biology experiments.