The GPCR Nobody Has Learned to Drug Yet — Schulte

Frizzled receptors look like GPCRs — but the field is split on whether they actually are. Gunnar Schulte has spent 25 years building the case, one receptor at a time.

Schulte is a professor at Karolinska Institute in Stockholm, where his lab investigates Wnt–frizzled signaling at the molecular level. His research maps G-protein coupling specificity across all 10 frizzled subtypes, develops conformational biosensors to detect receptor activation, and searches for small molecules that could finally make frizzled receptors pharmacologically tractable. In this conversation, he walks through the evidence — what the conformational data show, why the Wnt ligand problem has stalled the field for decades, and how a compound originally designed for Smoothened became the closest thing frizzled pharmacology has to a starting point.

• Why each frizzled subtype couples to a different G protein — and why that distinction changes how the field should think about targeting them
• Why 19 Wnt ligands remain almost impossible to work with, and what the lipid modification problem costs drug discovery
• How SAG1.3, a Smoothened agonist, became the first small molecule to activate frizzled 6 as a partial agonist
• What conformational sensors reveal about frizzled activation — and why Schulte considers this his strongest argument for their GPCR identity
• How disheveled and G proteins may compete for receptor access through conformational selection

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