G-protein coupled receptors (GPCRs) are important therapeutic targets for numerous human diseases. The understanding of GPCRs’ functional mechanisms has evolved from the simple differentiation of the active and inactive states to the characterizations of divergent active states responsible for partial or functionally selective signaling. High-resolution crystal structures of these proteins hold the promise to significantly enhance the outcomes of structure-based (rational) drug discovery efforts by providing the basis to tailor selectivity and efficacy. Indeed, a current focus of the field is on developing functionally biased ligands. On the other hand, using combined in silico and in vitro analyses, we proposed that Na+-sensitive and -insensitive antagonists of dopamine D2 and D3 receptors (D2R and D3R) stabilize the receptors in subtly but significantly different inactive conformations. However, among the available crystal structures of the aminergic GPCRs, no divergence in conformation has been detected for the inactive state for any individual receptor. Nevertheless, the structures of highly homologous D2R and D3R in the inactive states show significant differences on the extracellular side of the transmembrane domain when they are bound with non-selective antagonists of different scaffolds. Based on extensive molecular dynamics simulations (accumulated &gt; 0.3 ms) of D2R in complex with various antagonists, our analyses indicate that the structure of D2R/risperidone complex captures an inactive receptor conformation specifically accommodating the risperidone-like scaffold but not for some other scaffolds. In addition, our simulations reveal significant dynamics of the second extracellular loop of D2R, which is located on top of the ligand binding pocket. Our results highlight previously unappreciated conformational complexity for the inactive state of GPCRs and the new opportunities in the rational drug discovery targeting this state.

Inactive state of dopamine D2 receptor has multiple conformations

2019 Fall National Meeting

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