De novo design of light-controlled conformational protein switches

De novo computational design produced light-responsive proteins that bind retinal and undergo a defined light-activated conformational change, enabling heterodimers with over 30-fold increased binding upon illumination.

• Why it matters: Optogenetics is constrained by the limited number of natural and engineered photoreceptors, and designing native-like light-responsive proteins that couple chromophore chemistry to structural switching remains difficult.
• What they did: The work bottom-up designs de novo proteins to bind a retinal chromophore and couples retinal isomerisation to a conformational switching motion, then validates switching with real-time light-activated NMR.
• The result: The retinal-linked switch unlocks light-activated heterodimers with >30-fold binding increases and allows tuning of wavelengths, sensitivities, and specificities, which can regulate intracellular protein-protein interactions and cell-signalling receptors.