当前位置: X-MOL 学术Chem. Sci. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
High-throughput identification of G protein-coupled receptor modulators through affinity mass spectrometry screening†
Chemical Science ( IF 8.4 ) Pub Date : 2018-02-20 00:00:00 , DOI: 10.1039/c7sc04698g
Shanshan Qin 1, 2, 3, 4 , Mengmeng Meng 4, 5, 6, 7 , Dehua Yang 3, 8, 9, 10, 11 , Wenwen Bai 4, 5, 6, 7 , Yan Lu 1, 2, 3, 4, 12 , Yao Peng 1, 2, 3, 4 , Gaojie Song 1, 2, 3, 4 , Yiran Wu 1, 2, 3, 4 , Qingtong Zhou 1, 2, 3, 4 , Suwen Zhao 1, 2, 3, 4, 12 , Xiping Huang 13, 14, 15, 16, 17 , John D. McCorvy 13, 14, 15, 16, 17 , Xiaoqing Cai 3, 8, 9, 10, 11 , Antao Dai 3, 8, 9, 10, 11 , Bryan L. Roth 13, 14, 15, 16, 17 , Michael A. Hanson 17, 18, 19 , Zhi-Jie Liu 1, 2, 3, 4, 12 , Ming-Wei Wang 3, 8, 9, 10, 11 , Raymond C. Stevens 1, 2, 3, 4, 12 , Wenqing Shui 1, 2, 3, 4, 12
Affiliation  

G protein-coupled receptors (GPCRs) represent the largest class of cell surface proteins and thus constitute an important family of therapeutic targets. Therefore, significant effort has been put towards the identification of novel ligands that can modulate the activity of a GPCR target with high efficacy and selectivity. However, due to limitations inherent to the most common techniques for GPCR ligand discovery, there is a pressing need for more efficient and effective ligand screening methods especially for the identification of potential allosteric modulators. Here we present a high-throughput, label-free and unbiased screening approach for the identification of small molecule ligands towards GPCR targets based on affinity mass spectrometry. This new approach features the usage of target-expressing cell membranes rather than purified proteins for ligand screening and allows the detection of both orthosteric and allosteric ligands targeting specific GPCRs. Screening a small compound library with this approach led to the rapid discovery of an antagonist for the 5-HT receptor and four positive allosteric modulators for GLP-1 receptor that were not previously reported.

中文翻译:

通过亲和质谱筛选对G蛋白偶联受体调节剂进行高通量鉴定

G蛋白偶联受体(GPCR)代表了最大的细胞表面蛋白类别,因此构成了重要的治疗靶标家族。因此,已经致力于鉴定可以高效和选择性地调节GPCR靶标活性的新型配体。然而,由于最常见的GPCR配体发现技术固有的局限性,迫切需要更有效的配体筛选方法,尤其是用于识别潜在的变构调节剂。在这里,我们提出了一种基于亲和质谱的高通量,无标记且无偏见的筛选方法,用于识别针对GPCR目标的小分子配体。这种新方法的特点是使用表达靶标的细胞膜而不是纯化的蛋白进行配体筛选,并且可以检测靶向特定GPCR的正构和变构配体。用这种方法筛选小的化合物文库导致迅速发现了5-HT受体拮抗剂和GLP-1受体的四个阳性变构调节剂,这是以前没有报道的。
更新日期:2018-02-20
down
wechat
bug