9EPO

High resolution structure of FZD7 in inactive conformation

Summary for 9EPO

• Entry DOI: 10.2210/pdb9epo/pdb
• EMDB information: 19881
• Descriptor: Frizzled-7, CHOLESTEROL HEMISUCCINATE, PALMITIC ACID, ... (4 entities in total)
• Functional Keywords: gpcpr, frizzled, fzd7, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 137381.47

Authors

Bous, J.,Kinsolving, J.,Gratz, L.,Scharf, M.M.,Voss, J.,Selcuk, B.,Adebali, O.,Schulte, G. (deposition date: 2024-03-19, release date: 2024-10-02, Last modification date: 2025-04-09)

Primary citation

Bous, J.,Kinsolving, J.,Gratz, L.,Scharf, M.M.,Voss, J.H.,Selcuk, B.,Adebali, O.,Schulte, G.
Structural basis of frizzled 7 activation and allosteric regulation.
Nat Commun, 15:7422-7422, 2024

PubMed Abstract: Frizzleds (ten paralogs: FZD) belong to the class F of G protein-coupled receptors (GPCRs), which remains poorly understood despite its crucial role in multiple key biological functions including embryonic development, stem cell regulation, and homeostasis in the adult. FZD, one of the most studied members of the family, is more specifically involved in the migration of mesendoderm cells during the development and renewal of intestinal stem cells in adults. Moreover, FZD has been highlighted for its involvement in tumor development predominantly in the gastrointestinal tract. This study reports the structure of inactive FZD, without any stabilizing mutations, determined by cryo-electron microscopy (cryo-EM) at 1.9 Å resolution. We characterize a fluctuating water pocket in the core of the receptor important for FZD dynamics. Molecular dynamics simulations are used to investigate the temporal distribution of those water molecules and their importance for potential conformational changes in FZD. Moreover, we identify lipids interacting with the receptor core and a conserved cholesterol-binding site, which displays a key role in FZD association with a transducer protein, Disheveled (DVL), and initiation of downstream signaling and signalosome formation.

PubMed: 39198452
DOI: 10.1038/s41467-024-51664-4

Experimental method

ELECTRON MICROSCOPY (1.9 Å)