Rotation of the N-terminal helix triggers Gα activation.

Engagement with an active GPCR increases conformational displacement of the Gαs N-terminal helix (αN), and counterclockwise αN rotation facilitates GDP release.

• Why it matters: GPCR-triggered activation depends on GDP release from Gα, but beyond the C-terminal α5 helix, the role and mechanism of other Gα regions have been unclear.
• What they did: Using diffracted X-ray tracking plus biochemical assays and molecular dynamics simulations, the study tested how αN rotational conformational changes affect GDP release.
• The result: The αN-driven pathway works synergistically with α5 changes and propagates through the β-sheet network to the P-loop and αG helix, extending the mechanistic model for GPCR activation.

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