Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Nat Commun. 2023 Nov 22;14(1):7620. doi: 10.1038/s41467-023-43537-z.
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.
羟基羧酸是参与各种生理和病理过程的重要代谢中间产物，其中一些被特定的羟基羧酸受体（HCAR）识别。HCAR2 是这样的一种受体，被内源性的β-羟基丁酸（3-HB）和丁酸盐激活，也是烟酸的作用靶点。HCAR2 作为心血管和神经炎症性疾病的治疗靶点引起了人们的兴趣。然而，由于对配体与该受体结合的方式了解有限，因此难以开发出能够避免与烟酸治疗相关的常见潮红副作用的替代药物。在这里，我们展示了三种与四种不同配体结合的 HCAR2-Gi1 复合物的高分辨率结构，一种单独结合的有效合成激动剂（MK-6892），以及与别构激动剂化合物 9n 结合的两种结构，分别与内源性配体 3-HB 或烟酸结合。这些结构结合我们的功能和计算分析，进一步加深了我们对配体识别、别构调节和 HCAR2 激活的理解，为开发具有降低副作用的高效药物铺平了道路。
