Activation mechanisms of Class F GPCRs – from structural understanding to novel therapeutics

• Applicant: Dr. Hannes Schihada
• Subject Area: Pharmacology ; Structural Biology ; Cell Biology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427840891

The cells of living organisms have to be able to perceive and adopt to changes of their surrounding environment. These processes are mediated by membrane-embedded biomolecules and the family of G protein-coupled receptors (GPCRs) plays a major role within eukaryotic cells. Approximately 30% of all currently approved drugs address GPCRs and this class of cell surface receptors will continue to be in the focus of future drug discovery programs. Besides developing novel types of GPCR-directed drugs, one major strategy in modern drug discovery is to exploit yet untapped GPCR families as novel drug targets. One of these is the GPCR family class F, encompassing the ten Frizzled receptors (FZD1-10) and Smoothened (SMO). FZDs are involved in diverse pathophysiological processes and therefore represent attractive targets for the treatment of different tumours, inflammatory processes and neurodegenerative diseases. Unfortunately, our current understanding of this GPCR family is quite limited for several reasons. FZDs function as cell surface receptors for secreted Wingless/int1 (WNT) lipoglycoproteins which need to be purified under laborious biotechnological procedures. Thus, WNTs cannot serve as ideal pharmacological tools to explore structure and function of class F GPCRs. Furthermore, many aspects of FZD activation and subsequent receptor-mediated signalling remain unknown, leaving for instance the relevance of distinct FZD-mediated signalling cascades for the pathogenesis of different diseases in doubt. Moreover, despite significant progress over the last years, there is yet a strong disagreement in the WNT/FZD community on the (patho-)physiological relevance of G-protein-mediated FZD signalling. The lack of appropriate FZD ligands and advanced biochemical, as well as cell biological methods further hampers the investigation of such essential FZD functions and ultimately slows down the development of FZD-directed therapeutics. It’s the major goal of this project to develop advanced technologies to study class F GPCRs and employ these methods to pharmacologically characterize innovative FZD ligands. High potent FZD ligands, identified as such in the course of this project, will be evaluated for their ability to stabilise FZDs in specific receptor conformations and to make them accessible for subsequent structural studies of frizzled GPCRs through cryo-electronmicroscopy. The applicant has multi-year experience in GPCR assay development. Furthermore, the collaboration with the host-scientist, who is a pioneering researcher in the field of FZD pharmacology, as well as the integration into the excellent research infrastructure at the Karolinska Institute will enable promising synergies and allow for significant breakthroughs in FZD research. The insights of this study will not only affect subsequent structural studies of these receptors but also guide future FZD-directed drug discovery programs.

• DFG Programme: Research Fellowships
• International Connection: Sweden
• Host: Professor Gunnar Schulte, Ph.D.