A molecular mechanism of UDCA engagement with GPBAR and subsequent G protein interaction revealed by scattered alanine scanning
A molecular mechanism of UDCA engagement with GPBAR and subsequent G protein interaction revealed by scattered alanine scanning
复制标题
分散丙氨酸扫描揭示 UDCA 与 GPBAR 结合以及随后的 G 蛋白相互作用的分子机制
DOI：
10.1016/j.bbrc.2022.02.030
复制
发表时间：
2022
影响因子：
3.1
通讯作者：
Jiu-yao Zhou
中科院分区：
文献类型：
--
作者：
Ruirui Lu;Xu Yan;Guoxing Fang;Yuming Zhuang;Lulu Guo;Chao Zhang;Xiang Wu;Peng Xiao;Yiwen Cao;Fan Yang;Xiao Yu;Jin-peng Sun;Jiu-yao Zhou
熊去氧胆酸（UDCA）是熊胆汁酸中最知名的治疗成分，是FDA批准的治疗原发性胆汁性肝硬化（PBC）、溶解胆固醇结石的药物。UDCA通过与膜G蛋白偶联胆汁酸受体（GPBAR）的相互作用对代谢和免疫反应产生许多有益作用;然而，UDCA如何与GPBAR相互作用及其选择性细胞效应仍然难以捉摸。本研究采用丙氨酸散射扫描和分子对接的方法研究了UDCA与GPBAR的相互作用及其激活GPBAR的机制。我们的研究结果表明，GPBAR的跨膜螺旋2（TM 2），TM 3，TM 5和TM 6有助于UDCA在GPBAR结合口袋中的相互作用。推测UDCA的3-OH与GPBAR中Y2406.51的酚氧结合在GPBAR的活化中起关键作用。出乎意料的是，除了细胞内环2（ICL 2）残基的已知作用外，我们还发现ICL 3残基在G蛋白偶联GPBAR以响应UDCA结合中发挥重要作用。我们的研究提供了GPBAR如何识别UDCA以及随后的激活和G蛋白相互作用的初步分子机制，这可能有助于开发新的胆汁酸衍生物作为治疗药物。
As the most known therapeutic component of bear bile acids, ursodeoxycholic acid (UDCA) is an FDA-approved drug for the treatment of primary biliary cirrhosis (PBC), the dissolution of cholesterol gallstones. UDCA produces many beneficial effects on metabolism and immune responses via its interaction with the membrane G protein-coupled bile acid receptor (GPBAR); however, how UDCA interacts with GPBAR and its selective cellular effects remain elusive. In this study, we delineated the interaction of UDCA with GPBAR and activation mechanism of GPBAR by scattered alanine scanning and molecular docking. Our results indicated that transmembrane helix 2 (TM2), TM3, TM5 and TM6 of GPBAR contribute to the interaction of UDCA in GPBAR binding pocket. Moreover, we predicted that the engagement of the 3-OH of UDCA with phenolic oxygen of Y2406.51in GPBAR plays a key role in GPBAR activation. Unexpectedly, in addition to the well-known roles of intracellular loop2 (ICL2) residues, we identified that ICL3 residues play an important role in G protein coupling to GPBAR in response to UDCA binding. Our study provides a preliminary molecular mechanism of how GPBAR recognizes UDCA and subsequent activation and G protein interaction, which may facilitate the development of new bile acid derivatives as therapeutics.