Energetic analysis of the R*-G complex links the α5 helix to GDP release and domain opening

We present a model of interaction of G(i) protein with activated rhodopsin (R*) which pin-points energetic contributions to activation and reconciles the β(2)AR–G(s) crystal structure with new and previously published experimental data. In silico analysis demonstrated energetic changes when the Gα C-terminal helix (α5) interacts with the R* cytoplasmic pocket, leading to displacement of the helical domain and GDP release. The model features a less dramatic domain opening than the crystal structure. The α5 helix undergoes a 63º rotation, accompanied by a 5.7Å translation, which reorganizes interfaces between α5 and α1 helices and between α5 and β6–α5. Changes in the β6–α5 loop displace αG. All of these movements lead to opening of the GDP binding pocket. The model creates a roadmap for experimental studies of receptormediated G protein activation.