Delving into the Latest Updates on ConfometRx, Inc. with Synapse

作者: Lebon, Florence ; Ceska, Tom ; Kobilka, Tong Sun ; Bachhawat, Priti ; Chu, Matthew Ling-Hon ; Sands, Zara A. ; Wood, Martyn ; Sun, Bingfa ; Kobilka, Brian K. ; Mercier, Joel

Significance The A 2A R is a G protein-coupled receptor (GPCR) that plays important roles in cardiovascular physiology and immune function. The A 2A R is also a target for the treatment of Parkinson’s disease, where A 2A R antagonists have been shown to enhance signaling through the D2 dopamine receptor. Here we present the crystal structure of the A 2A R bound to a novel bitopic antagonist. As a result of structural changes needed to accommodate the bound antagonist, crystals could not be grown in lipidic cubic phase. Instead, crystals were grown in detergent with a type II packing rarely observed in GPCR crystals. The structure revealed a potential allosteric pocket that that can be exploited to develop subtype-selective allosteric modulators.

Nature Communications1区 · 综合性期刊

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

1区 · 综合性期刊

ArticleOA

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

AbstractDopamine 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.

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Metabolic disease therapy (ConfometRx) ( GPCR )	代谢性疾病更多	临床阶段不明
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