Conformational restriction of G‐proteins Coupled Receptors (GPCRs) upon complexation to G‐proteins: A putative activation mode of GPCRs?

GPCRs undergo large conformational changes during their activation. Starting from existing X‐ray structures, we used Normal Modes Analyses to study the collective motions of the agonist‐bound β2‐adrenergic receptor both in its isolated “uncoupled” and G‐protein “coupled” conformations. We interestingly observed that the receptor was able to adopt only one major motion in the protein:protein complex. This motion corresponded to an anti‐symmetric rotation of both its extra‐ and intra‐cellular parts, with a key role of previously identified highly conserved proline residues. Because this motion was also retrieved when performing NMA on 7 other GPCRs which structures were available, it is strongly suspected to possess a significant biological role, possibly being the “activation mode” of a GPCR when coupled to G‐proteins.