G protein-coupled receptors (GPCRs), central to signal transduction and ever-popular as drug targets, are known to contain internal water molecules. How these water molecules contribute to GPCR function, however, has been unclear, despite the accumulation of 3D GPCR structures. Unfortunately, these structures, obtained by means of X-ray crystallography, offer only static images. They give little indication of the ways a GPCR’s internal waters may ebb and flow during the activation/deactivation cycle.

Lacking anything so convenient as a molecular-scale dowser, researchers centered at the Ecole Polytechnique Fédérale de Lausanne (EPFL) resorted to computer simulations. Specifically, the researchers used molecular dynamics simulation to monitor, “at atomic and high temporal resolution,” conformational changes of central importance for the activation of three prototypical GPCRs.

For each of the three GPCRs—the adenosine A2A receptor, the β2-adrenergic receptor, and rhodopsin—the researchers had the benefit of existing crystal structures. The researchers, however, were determined to go further, tracing the conformational changes that occur during the process of signal transduction.

While modeling these conformational changes, the researchers, led by EPFL’s Horst Vogel, took notice of a layer of amino acid residues. This layer, which is located next to a conserved structural motif called NPxxY, is hydrophobic, and so it acts a kind of water barrier. Upon receptor activation, however, the barrier acts more like a gate, opening to form a continuous water channel that extends from the ligand binding site to the intracellular region of the receptor.

This finding appeared September 9 in Nature Communications, in an article entitled, “Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway.”

“The highly conserved tyrosine residue Y7.53 undergoes transitions between three distinct conformations representative of inactive, G-protein activated, and GPCR metastates,” wrote the authors. This sequence of conformational changes, which take place during GPCR activation, coincides with the formation of the water channel within the GPCR.

Interfering with water channel formation by deploying appropriately designed therapeutics could modify GPCR function.

“This discovery of these internal water channels can pave the way for novel approaches in drug development,” said Horst Vogel. “By searching for compounds which bind to GPCRs and modulate their water channels, it might be possible to find more efficient therapeutic compounds.”