Significance Although G-protein–coupled receptors (GPCRs) control vast physiological pathways, their activation remains chemically and physically enigmatic. Our osmotic stress studies of the visual receptor rhodopsin have redefined the standard model of GPCR signaling by revealing the essential role of bulk water. We show results consistent with a large number of water molecules flooding the rhodopsin interior during activation to stabilize the effector binding conformation. These results suggest a model of GPCR activation in which the receptor becomes solvent-swollen upon formation of the active state. We thus demonstrate the mechanism whereby water acts as a powerful allosteric modulator of a pharmacologically important membrane protein family.

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The T-cell antigen receptor (TCR) initiates immune responses by recognising a wide variety of foreign peptides presented by Major Histocompatibility Complex (MHC) proteins. The TCR consists of non-covalently associated TCRab, CD3εg, CD3εd and zz dimers. The CD3 and zz subunits have long intracellular

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