Opioid receptor random mutagenesis reveals a mechanism for G protein–coupled receptor activation

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Abstract
The high resolution structure of rhodopsin has greatly enhanced current understanding of G protein–coupled receptor (GPCR) structure in the off-state, but the activation process remains to be clarified. We investigated molecular mechanisms of δ-opioid receptor activation without a preconceived structural hypothesis. Using random mutagenesis of the entire receptor, we identified 30 activating point mutations. Three-dimensional modeling revealed an activation path originating from the third extracellular loop and propagating through tightly packed helices III, VI and VII down to a VI-VII cytoplasmic switch. N- and C-terminal determinants also influence receptor activity. Findings for this therapeutically important receptor may apply to other GPCRs that respond to diffusible ligands.