Resolving conformational changes in membrane receptors in response to stimuli and capturing their dynamics is challenging. This challenge has been addressed through various spectroscopic methods applied to photoreceptors, often in natural membranes or Lipodisqs™. Recently, these studies have been expanded with functional assays, mass spectrometry, high-resolution crystallography (1.07Å), and XFELs, all without detergents and incorporating natural lipids. Findings reveal that water networks are critical in receptor activation and desensitization. In particular, the unique internal water arrangement in achearhodopsin-3 (AR3), a widely used photoreceptor in optogenetics, enables ~10x faster kinetics than bacteriorhodopsin. These insights may have broader implications for other receptors.

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