GDP Release from the Open Conformation of Gα Requires Allosteric Signaling from the Agonist-Bound Human β Adrenergic Receptor.

G-protein-coupled receptors (GPCRs) transmit signals into the cell in response to ligand binding at its extracellular domain, which is characterized by the coupling of agonist-induced receptor conformational change to guanine nucleotide (GDP) exchange with guanosine triphosphate on a heterotrimeric (αβγ) guanine nucleotide-binding protein (G-protein), leading to the activation of the G-protein. The signal transduction mechanisms have been widely researched and . However, coordinated communication from stimulating ligands to the bound GDP still remains elusive. In the present study, we used microsecond (μS) molecular dynamic (MD) simulations to directly probe the communication from the β adrenergic receptor (βAR) with an agonist or an antagonist or no ligand to GDP bound to the open conformation of the Gα protein. Molecular mechanism-general Born surface area calculation results indicated either the agonist or the antagonist destabilized the binding between the receptor and the G-protein but the agonist caused a higher level of destabilization than the antagonist. This is consistent with the role of agonist in the activation of the G-protein. Interestingly, while GDP remained bound with the Gα-protein for the two inactive systems (antagonist-bound and apo form), GDP dissociated from the open conformation of the Gα protein for the agonist activated system. Data obtained from MD simulations indicated that the receptor and the Gα subunit play a big role in coordinated communication and nucleotide exchange. Based on residue interaction network analysis, we observed that engagement of agonist-bound βAR with an α5 helix of G is essential for the GDP release and the residues in the phosphate-binding loop, α1 helix, and α5 helix play very important roles in the GDP release. The insights on GPCR-G-protein communication will facilitate the rational design of agonists and antagonists that target both active and inactive GPCR binding pockets, leading to more precise drugs.