Structural basis for inefficient G protein coupling by Frizzled receptors

Cryo-EM structures of FZD7–Gs and FZD5–Gq identify LMNG as a detergent bridge that stabilizes a weak, shallow receptor–G protein interface.

• Why it matters: Agonist-free FZD–G protein structures conflict with the difficulty of detecting coupling in cells, and unassigned density left the mechanism unclear.
• What they did: Using single-particle cryo-EM, the authors assign the interfacial density to LMNG, then test complex stability by removing LMNG in biochemical preparations and molecular dynamics simulations.
• The result: Without LMNG, the FZD–G protein complex destabilizes, indicating constitutive engagement is intrinsically weak and that a conserved intracellular interface mutation differentially affects DVL versus G protein signalling.

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