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Swiss Society for Crystallography - Howard Flack Crystallographic Lectures Series

Online Archiv

15. March 2021, 16:00 17:00

Online via Zoom

Invited Talk

SwissFEL adventures in room-temperature crystallography: From the structure of vertebrate and invertebrate rhodopsins to new applications in optogenetics

 

Speaker: Prof. Dr. Gebhard Schertler

Host: Prof. Dr. Antonia Neels, President of the Swiss Society for Crystallography SSCr

 

Abstract

We explore the use of light switchable G protein-coupled receptors (GPCRs) ­for the development of new optogenetic tools to control cellular signalling processes using light: OptoGPCRs. In a first stage, we identified several new opsins triggering GPCR signalling pathways. We extensively characterized the most promising candidates of invertebrate opsins biochemically in cellular assays and finally in vivo. We developed the basis for engineering bistable opsins, light switchable opsins, towards more effective optogenetic tools that are applicable in a very wide range of physiological processes. We determined the structure of a recombinant invertebrate rhodopsin and we carried out a detailed study of the chromophore binding site with advanced biophysical and crystallographic methods. In the case of vertebrate rhodopsins, we were able to use SwissFEL to observe directly the retinal isomerization with room-temperature serial crystallography. We were able to compare in detail monostable and bistable visual pigments. The bistable pigments in several aspects are closer to the ligand binding pharmacologically relevant GPCRs. In a successful engineering attempt, we were able to identify mutations that shift the wavelengths of an invertebrate rhodopsin towards the infrared or UV. This is important for the depth of penetration of light into tissues and for the ability to switch singalling ON and OFF with different light colours. The engineered OptoGPCRs are an important alternative to the channel opsins related optogenetic tools. OptoGPCRs have a wide range of applications that are not restricted to neurons. In future work, we can include the information we gained from single particle cryo-EM studies of rhodopsin / G protein singalling complexes. This will enable us to engineer the signalling output of the newly designed OptoGPCRs. These new tools have the potential to revolutionize many biologically important areas of medical science.

 

About the speaker

 

Prof. Dr. Gebhard Schertler heads the PSI Division of Biology and Chemistry (BIO) and is Professor of Structural Biology at the ETH Zürich (D-BIOL). He joined PSI in 2010 and became a member of the directorial board of PSI in 2011. He received his PhD at the University of Munich where he built his expertise in structural biology of membrane proteins and molecular pharmacology. He was at the MRC-LMB in Cambridge, UK, as a group leader until 2009. His research focus are G protein coupled receptors (GPCRs) and retinal proteins. He is a world-leading structural biologist of membrane proteins with expertise in biophysical methods, electron microscopy, and X-ray crystallography including time-resolved measurements at Synchrotrons and Free Electron Lasers. He initiated the Free Electron Laser biology research program at PSI. He is a member of the electron detector consortium headed by Richard Henderson and he was on the Scientific Advisory Committee of MAX IV Laboratory, Sweden. His experience with translating research resulted into business opportunities. He is a scientific founder of MRC-LMB Spin-Off Heptares Ltd., and he a co-founded InterAx AG and leadXpro AG, two Biotech companies at the PSI in 2015 and 2016 in context with Park InnovAare. In 2021 he obtained and coordinates an ERC Synergy Grant on Switchable rhodOpsins in Life Sciences (SOL). OptoGPCRs will open new opportunities in life sciences and medical research.