Structure-guided development of heterodimer-selective GPCR ligands.
Structure-guided development of heterodimer-selective GPCR ligands.
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杂化二聚体选择性GPCR配体的结构引导的发展。
DOI：
10.1038/ncomms12298
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发表时间：
2016-07-26
影响因子：
16.6
通讯作者：
Gmeiner P
中科院分区：
文献类型：
--
作者：
Hübner H;Schellhorn T;Gienger M;Schaab C;Kaindl J;Leeb L;Clark T;Möller D;Gmeiner P
G蛋白偶联受体（GPCR）配体复合物的晶体结构允许新的分子探针和药物的合理设计。本文报道了多巴胺D2受体/神经降压素NTS 1受体（D2 R/NTS 1 R）异二聚体双价配体的结构设计、化学合成和生物活性研究。1-3型化合物由三种不同的D2 R药效团组成，它们与产生亲和力的亲脂性附件、基于聚乙二醇的接头和NTS 1 R激动剂NT结合（8- 1 - 3）。与仅表达D2 R的细胞相比，二价配体对共表达GPCR和前所未有的选择性（高达三个数量级）的细胞显示出皮摩尔范围内的结合亲和力。观察到二价配体3b，c在单独表达D2 R的细胞中抑制cAMP形成但在D2 R/NTS 1 R共表达细胞中刺激cAMP积累的功能开关。此外，新合成的二价配体在D2 R/NTS 1 R共表达细胞中显示出强的、主要是NTS 1 R介导的β-抑制蛋白-2募集。 G蛋白偶联受体（GPCR）参与关键信号通路，是治疗神经和精神疾病的重要靶点。在这里，作者描述了有效结合治疗相关GPCR异二聚体的强大二价配体
Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design of novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers. The compounds of types 1–3 consist of three different D2R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1R agonist NT(8-13). The bivalent ligands show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity (up to three orders of magnitude), compared with cells that only express D2Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated β-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells. G protein-coupled receptors (GPCRs) are involved in key signalling pathways and represent important targets for the treatment of neurological and psychiatric disorders. Here, the authors describe powerful bivalent ligands that efficiently bind to therapeutically relevant GPCR heterodimers