Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist

Bingfa Sun,Matthew Ling-Hon Chu,Martyn Wood,Sebastian Kelm,Dan Feng,Zara A Sands,Florence Lebon,Tong Sun Kobilka,Anne Valade,Tom Ceska,Inbar Fish,Silvia Lovera,Brian K Kobilka

doi:10.1038/s41467-021-23519-9

Abstract

Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist.

Highlights

Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders
Dopamine receptors are a family of G protein-coupled receptors (GPCRs) with five subtypes, which can be further divided into D1-like (D1R, D5R) and D2-like (D2R, D3R, and D4R) subfamilies based on their sequence similarities and G protein coupling specificity[1,2]
D1R is in a fully active conformation, featured by an open conformation of the cytoplasmic end of TM6 and active-state specific conformations of DRY and NPXXY motifs, which are conserved throughout family-A GPCRs (Fig. 1b and Supplementary Fig. 1b)[21,22]

Summary

Introduction

Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Prolonged exposure to these agonists results in tachyphylaxis in vivo due to desensitization caused by the activation of the arrestin pathway as mentioned above[6,7,8] These drawbacks limit the potential of therapeutic application of these compounds. A class of non-catechol agonists was reported with an interesting efficacy profile[6,17,18] They are highly selective towards D1R and D5R, versus other dopamine receptor subtypes and closely related aminergic receptors[17]. As a result of their functional selectivity, they caused little or no internalization of D1R in cells and have more sustained behavioral activity in animal models[6] These results highlighted the potential of non-catechol agonists when targeting D1R for therapeutic purposes. The structure reveals unique features of the Compound 1 binding pocket in D1R and provides insights into the subtype selectivity of this scaffold, and the mechanism of D1R activation in the absence of a catechol moiety

Methods

Results

Conclusion