冷冻电镜结构揭示了IGF1R的多态性配体结合状态。

Cryo-EM Structure Reveals Polymorphic Ligand-bound States of IGF1R.

作者信息

Zhang Xi, Wei Tianzi, Wu Cang, Jiang Junyi, Chen Shengming, Hu Yinqing, Lu Yi, Sun Dayong, Zhai Liting, Zhang Jian, Liu Chuang

机构信息

Department of Gastroenterology, The First Affiliated Hospital of Shenzhen University, Shenzhen People's Second Hospital, Shenzhen 518000, Guangdong, China; Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China; Cryo-EM Centre, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.

Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, Hong Kong Special Administrative Region.

出版信息

J Mol Biol. 2022 May 15;434(9):167536. doi: 10.1016/j.jmb.2022.167536. Epub 2022 Mar 15.

DOI:10.1016/j.jmb.2022.167536

PMID:35300993

Abstract

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in regulating cellular metabolism and cell growth and has been identified as an anticancer drug target. Although previous studies have revealed some structures of IGF1R with different ligands, the continuous dynamic conformation change remains unclear. Here, we report 10 distinct structures (7.9-3.6 Å) of IGF1R bound to IGF1 or insulin to reveal the polymorphic conformations of ligand-bound IGF1R. These results showed that the α-CT, disulfide bond (C670-C670'), and FnIII-2 domains had the most flexible orientations for the conformational change that occurs when ligands bind to the receptor. In addition, we found one special conformation (tentatively named the diverter-switch state) in both complexes, which may be one of the apo-IGF1R forms under ligand-treatment conditions. Hence, these results illustrated the mechanism of how different ligands could bind to human IGF1R and provided a rational template for drug design.

摘要

1型胰岛素样生长因子受体（IGF1R）在调节细胞代谢和细胞生长中起重要作用，并且已被确定为抗癌药物靶点。尽管先前的研究已经揭示了IGF1R与不同配体结合的一些结构，但连续的动态构象变化仍不清楚。在这里，我们报告了与IGF1或胰岛素结合的IGF1R的10种不同结构（7.9 - 3.6 Å），以揭示配体结合的IGF1R的多态构象。这些结果表明，α-CT、二硫键（C670 - C670'）和FnIII-2结构域在配体与受体结合时发生的构象变化中具有最灵活的取向。此外，我们在两种复合物中都发现了一种特殊构象（暂命名为转向开关状态），这可能是配体处理条件下脱辅基IGF1R的形式之一。因此，这些结果阐明了不同配体如何与人IGF1R结合的机制，并为药物设计提供了合理的模板。