Gprotein-coupled receptors (GPCRs) are the largest family of membrane receptor proteins and the target of most pharmaceuticals made today. The first step in the activation mechanism of most GPCRs is the binding of a signaling ligand. Ligand binding to the extracellular loops or within the transmembrane helical bundle of these receptors leads to an allosteric conformational change that promotes G protein activation. The precise location of the activating ligand and the conformational changes triggered by ligand binding are unknown for any GPCR.

Our research on signal transduction mechanisms mediated by GPCRs mainly involves the visual pigment rhodopsin. Rhodopsin is the receptor in vertebrate rod cells responsible for vision in dim light. However, we have recently begun structural studies on CCR5, a chemokine receptor in T-cells, and the b2-adrenoreceptor. The b2-adrenoreceptor mediates physiological responses to adrenaline and noradrenaline, and plays a critical role in the regulation of the cardiovascular system.

Rhodopsin consists of a bundle of seven transmembrane helices that surround the photoreactive chromophore, 11-cis retinal. Absorption of a single photon of light is sufficient to isomerize the retinal from cis to trans, and activate the protein. Using solid-state NMR spectroscopy, we can define the position of the retinal in the active and inactive states of rhodopsin, and the structural changes within the retinal binding site that lead to receptor activation. The location of the retinal in activated rhodopsin and its interaction with sequence motifs that are highly conserved across the pharmaceutically important class A GPCR family has provided the basis for a general mechanism of GPCR activation. he structure