Conserved waters mediate structural and functional activation of family A (rhodopsin-like) G protein-coupled receptors

Oct. 9, 2009

G protein-coupled receptors with seven transmembrane α helices (GPCRs) are membrane proteins that mediate signal transduction by recognizing a wide range of extracellular stimuli ranging from photons of light, biogenic amines and odorants, to small peptides that all induce receptor activation. Activated GPCRs signal through heterotrimeric G proteins to activate effector enzymes resulting in rapid signal amplification. The availability of high-resolution crystal structures of five prototypical GPCRs, bovine and squid rhodopsin, engineered A2A-adenosine, β1- and β2-adrenergic receptors, permits comparative analysis of features common to these and likely all GPCRs. We provide a novel analysis of the distribution of water molecules in the transmembrane region of these GPCR structures and find conserved contacts with microdomains previously demonstrated to be involved in receptor activation. Co-localization of water molecules associating with highly conserved and functionally important residues in several of these GPCR crystal structures supports the notion that these waters are likely to be as important to proper receptor function as the conserved residues. Moreover, in the absence of large conformational changes in rhodopsin following photoactivation, we propose that ordered waters contribute to the functional plasticity needed to transmit activation signals from the retinal-binding pocket to the cytoplasmic face of rhodopsin and that fundamental features of the mechanism of activation, involving these conserved waters, are shared by many if not all family A receptors.

Figure 1.

A structural superpositioning diagram of high-resolution crystal structures of bovine rhodopsin (red), squid rhodopsin (wheat), mutant β1-adrenergic receptor (light blue), mutant β2-adrenergic receptor (navy blue) and bovine opsin (grey) demonstrating a high level of overall structural similarity. Also shown are those water molecules that co-localize in the transmembrane helices.

Results from: Angel, T., Chance, M.R., and Palczewski, K. Conserved waters mediate structural and functional activation of family A (rhodopsin-like) G protein-coupled receptors, Proc. Nat. Acad. Sci., 106(21):8555-60, 2009.