Figure 4. Pathways in the activation mechanism of β₂AR.

This figure represents epinephrine (shown as spheres) bound to the β₂AR (TM5, green; TM6, blue; TM7/helix 8, cyan). Receptor activation comprises a series of conformational changes that aggregate into specific activation pathways. Agonists interact with a group of Ser residues on the extracellular side of TM5 (Ser203(5.42), Ser204(5.43) and Ser207(5.46)) involved in ligand binding and receptor activation (44, 45). This interaction disrupts the TM3/TM5 interface at the binding site (35), and these local changes are transmitted to the cytoplasmic side of the helix through the rearrangement of the Pro-induced distortion of TM5 (green arrow) (Sansuk et al., Mol Pharmacol under review)(47). Agonists also induce/stabilize the rigid body movement of TM6 (blue arrow) through their action on Trp(6.48). A complex hydrogen bond network between highly conserved residues and a cluster of water molecules in the TM2-TM6-TM7 interface seems responsible for stabilizing the pi-helix segment observed in the inactive state of rhodopsin(26). This network is most likely conserved in other Class A GPCRs (1), and has a structural and functional role (34). Specifically, we suggest that agonist binding induces changes in this network, which results in local structural changes in the NPxxY motif and in a relocation of the cytoplamic side of TM7 (cyan arrow). These pathways involve highly conserved residues, and are probably conserved in other Family A GPCRs. This figure has been created with PyMOL (DeLano, W.L. The PyMOL Molecular Graphics System (2002) on World Wide Web http://www.pymol.org).