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TitleStructural basis of frizzled 7 activation and allosteric regulation.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 7422, Year 2024
Publish dateAug 28, 2024
AuthorsJulien Bous / Julia Kinsolving / Lukas Grätz / Magdalena M Scharf / Jan Hendrik Voss / Berkay Selcuk / Ogün Adebali / Gunnar Schulte /
PubMed AbstractFrizzleds (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 ...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.
External linksNat Commun / PubMed:39198452 / PubMed Central
MethodsEM (single particle)
Resolution1.9 - 3.2 Å
Structure data

EMDB-19881, PDB-9epo:
High resolution structure of FZD7 in inactive conformation
Method: EM (single particle) / Resolution: 1.9 Å

PDB-9ew2:
High resolution structure of FZD7 in complex with miniGs protein
Method: ELECTRON MICROSCOPY / Resolution: 3.2 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-PLM:
PALMITIC ACID

ChemComp-HOH:
WATER

Source
  • Spodoptera frugiperda (fall armyworm)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCPR / Frizzled / FZD7

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