Activation mechanisms of Class Frizzled receptors
Title: Activation mechanisms of Class Frizzled receptors
SNIC Project: SNIC 2020/13-36
Project Type: SNIC Small Compute
Principal Investigator: Ainoleena Turku <ainoleena.turku@ki.se>
Affiliation: Karolinska Institutet
Duration: 2020-05-01 – 2021-05-01
Classification: 30102
Homepage: https://ki.se/en/fyfa/schulte-lab
Keywords:

Abstract

Cellular communication is accomplished by the release of soluble factors from one cell and reception of the molecule on the same or another cell through a pharmacological receptor. One of the largest receptor family are the G protein-coupled receptors, which are localized in the cell membrane to receive physiologically relevant instructions by molecules such as adrenaline, histamine, serotonin, dopamine, odorants, and many more. There are about 800 different human GPCRs critically involved in regulating basically every process in our body. Many of those receptors are already targeted by well-established drugs to treat human disease; approximately 30% of FDA approved drugs act via GPCRs. In the applied project, we focus on a special group of 11 GPCRs compiled in the class Frizzled (or class F), which consists of Smoothened (SMO) and ten different Frizzleds (FZD1-10). Despite the fact that FZDs present attractive drug targets due to their central role in many different forms of cancer, fibrosis, cardiovascular disease or neurological disorders, no small molecule drugs have been developed to target FZDs. This lack of drugs originates in the poor understanding of how Class F receptors are activated. The aims of this proposal are: (1) to understand molecular details of class F receptor activation, (2) to employ the new knowledge to improve and adapt high-throughput screening-compatible assays of receptor activation, (3) to define small molecules targeting FZDs using in silico docking and physical drug screens, and (4) to optimize found hit compounds with regard to receptor-interaction mode and drug effects on cell biology to define the compound’s mode of action, selectivity and risk for off-target side effects. The new knowledge emerging from this project will shed light on molecular activation mechanism of these receptors to understand receptor function and to directly employ the knowledge for a mechanism-based and structure-guided drug discovery process.