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Orthosteric and allosteric modulation of human HCAR2 signaling complex
Nature Communications ( IF 14.7 ) Pub Date : 2023-11-22 , DOI: 10.1038/s41467-023-43537-z
Chunyou Mao 1, 2, 3 , Mengru Gao 4, 5 , Shao-Kun Zang 1 , Yanqing Zhu 1 , Dan-Dan Shen 1, 6 , Li-Nan Chen 1, 7 , Liu Yang 4 , Zhiwei Wang 4 , Huibing Zhang 3 , Wei-Wei Wang 3 , Qingya Shen 3 , Yanhui Lu 8 , Xin Ma 4, 5 , Yan Zhang 1, 2, 3, 6
Affiliation  

Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.



中文翻译:


人 HCAR2 信号转导复合物的正构和变构调节



羟基羧酸是参与各种生理和病理过程的重要代谢中间体,其中一些被特异性羟基羧酸受体 (HCAR) 识别。HCAR2 就是这样一种受体,由内源性 β-羟基丁酸酯 (3-HB) 和丁酸盐激活,并且是烟酸的靶标。人们对 HCAR2 的兴趣源于其作为心血管和神经炎症性疾病治疗靶点的潜力。然而,对配体如何与该受体结合的有限了解阻碍了能够避免与烟酸治疗相关的常见潮红副作用的替代药物的开发。在这里,我们提出了与四种不同配体结合的 HCAR2-Gi1 复合物的三种高分辨率结构,一种有效的合成激动剂 (MK-6892) 单独结合,以及与变构激动剂化合物 9n 结合的两种结构与内源性配体 3-HB 或烟酸结合。这些结构加上我们的功能和计算分析,进一步加深了我们对配体识别、变构调节和 HCAR2 激活的理解,并为开发副作用更少的高效药物铺平了道路。

更新日期:2023-11-22
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