Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes

•Structures of DRD1-Gs in complex with catechol-based and non-catechol agonists •Key polar interaction network is involved in DRD1 activation •Specific features for agonists interaction and Gs coupling of DRD1 are determined •Structure of DRD1-Gs complexed with dopamine and positive allosteric modulator •Structural basis of allosteric regulation of DRD1 by LY3154207 is investigated Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1. Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1. Structural insights into the human D1 and D2 dopamine receptor signaling complexesZhuang et al.CellFebruary 10, 2021In BriefNear-atomic resolution structures of activated D1R-Gs and D2R-Gi signaling complexes, together with multiple functional studies, reveal the conserved catechol agonist binding mode in D1R and the structural basis that underlies D1R and D2R ligand selectivity and G protein-coupling specificity. Full-Text PDF