W2466.48 Opens a Gate for a Continuous Intrinsic Water Pathway during Activation of the Adenosine A2A Receptor

The question how G‐protein‐coupled receptors transduce an extracellular signal by a sequence of transmembrane conformational transitions into an intracellular response remains to be solved at molecular detail. Herein, we use molecular dynamics simulations to reveal distinct conformational transitions of the adenosine A_2A receptor, and we found that the conserved W246^6.48 residue in transmembrane helix TM6 performs a key rotamer toggle switch. Agonist binding induces the sidechain of W246^6.48 to fluctuate between two distinct conformations enabling the diffusion of water molecules from the bulk into the center of the receptor. After passing the W246^6.48 gate, the internal water molecules induce another conserved residue, Y288^7.53, to switch to a distinct rotamer conformation establishing a continuous transmembrane water pathway. Further, structural changes of TM6 and TM7 induce local structural changes of the adjacent lipid bilayer.