Nature Communications ( IF 14.7 ) Pub Date : 2024-06-25 , DOI: 10.1038/s41467-024-49536-y
Aslihan Shenol 1 , Ricardo Tenente 1 , Michael Lückmann 1 , Thomas M Frimurer 1 , Thue W Schwartz 1
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A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.
中文翻译：
最近的多个 HCAR2 结构展示了高度动态的配体结合和 G 蛋白激活模式
羟基羧酸受体 2 (HCAR2) 与八种不同的正构和一个复合物的三十个新颖 3D 结构的谜题揭示了连接 G 蛋白偶联受体激动剂与 G 蛋白结合以及反向连接的变构机制的令人惊讶的清晰图景。单一变构激动剂。 HCAR2 是 β-羟基丁酸、烟酸和某些抗炎药物的传感器。令人惊讶的是，有或没有靶向副作用的激动剂的结合非常相似，并且在完全闭塞的正位结合位点中。因此，尽管有许多结构，我们仍然需要了解该系统和类似系统的分子动力学。
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