Molecular modelling studies on Frizzled receptors
Title: Molecular modelling studies on Frizzled receptors
SNIC Project: SNIC 2021/5-490
Project Type: SNIC Medium Compute
Principal Investigator: Gunnar Schulte <gunnar.schulte@ki.se>
Affiliation: Karolinska Institutet
Duration: 2021-11-01 – 2022-11-01
Classification: 30102 10601
Homepage: http://ki.se/en/fyfa/receptor-biology-and-signaling
Keywords:

Abstract

G protein-coupled receptors (GPCRs) mediate effects of many endogenous and exogenous substances such as small molecules, peptides, lipids, ions, and odorants. According to homology, GPCRs were grouped into Classes A, B, C, F (Frizzleds), adhesion receptors, and other 7 transmembrane (TM) spanning receptors. Frizzleds (FZDs) regulate some processes during embryonic development, stem cell regulation, and adult tissue homeostasis. Deregulation of FZDs leads to pathogenesis, including, but not limited to, cancer and neurologic disorders; thus, making them attractive drug targets. In mammals, there are 10 Frizzleds (FZD1–10), which are activated by the WNT family of lipoglycoproteins through interaction with the extracellular cysteine-rich domain (CRD) of FZD. Our group was instrumental in promoting the understanding of molecular underpinnings of FZD activation including ligand-induced and constitutive activity. Our work has identified molecular switch mechanisms based on cancer genomics and receptor function, which has led to further development of FZD-centered assays with potential appliccability for drug screening and discovery. We plan to further our understanding of molecular mechanisms of FZD activation and signal initiation by analysis of ligand bvinding, receptor dynamics and effector coupling. We foresee that understanding the molecular details of receptor conformational changes will provide the basis to understand how FZDs define pathway selectivity in a class-wide manner, i. e. how FZDs can for example couple to the scaffold protein or heterotrimeric G proteins. We are planning to carry on the molecular dynamics (in general all-atom but we may also use coarse grained and other accelerated methods for larger systems) simulations of FZDs but potentially also of other proteins communicating with FZDs, e.g., DVL, heterotrimeric G proteins. The work is also planned to expand on other Class F representatives, such as SMO, FZD7 and other FZD paralogues. Our new models are instructed by better structural and functional insights and will be used for in silico screening of large databases of small molecules. The ligands with the lowest binding energies and highest docking scores are validated using all-atom molecular dynamics simulations. In order to target FZDs pharmacologically, we need to define the binding modes of the ligands in the orthosteric binding pocket of the receptor. The new information will be used to mutate residues that form essential interactions (e.g., hydrogen bonds) with ligands. Subsequently, these FZDs mutants will be tested for their cell membrane expression and used in functional studies that will aid in defining the ligand-protein interaction, ligand-receptor selectivity and guide further hit optimization. During 2021 we have published several high-impact papers , in which we have used SNIC resources. These publications are a continuation of the strong publication record from previous years, where we started to combine in silico and wet lab approaches, including two Nature Communications papers published in 2019 and 2020. Links to the published papers (except for the Science Advances paper currently in press): https://www.nature.com/articles/s41422-021-00525-6.pdf https://www.nature.com/articles/s41467-021-24004-z.pdf https://www.science.org/doi/epdf/10.1126/sciadv.abi6856