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

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

doi:10.1016/j.jmb.2022.167536

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

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

Authors

Xi Zhang¹, Tianzi Wei², Cang Wu³, Junyi Jiang³, Shengming Chen³, Yinqing Hu⁴, Yi Lu⁵, Dayong Sun⁶, Liting Zhai⁷, Jian Zhang⁸, Chuang Liu⁹

Affiliations

¹ 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.
² 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.
³ Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
⁴ Department of Gastroenterology, The First Affiliated Hospital of Shenzhen University, Shenzhen People's Second Hospital, Shenzhen 518000, Guangdong, China.
⁵ School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
⁶ Department of Gastroenterology, The First Affiliated Hospital of Shenzhen University, Shenzhen People's Second Hospital, Shenzhen 518000, Guangdong, China. Electronic address: dayongsunsz@163.com.
⁷ ChEM-H/Neuroscience Research Complex290 Jane Stanford Way, Stanford University, Stanford, CA 94305, USA. Electronic address: ltzhai@stanford.edu.
⁸ School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China. Electronic address: zhangjian@sustech.edu.cn.
⁹ Cryo-EM Centre, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China. Electronic address: liuc7@sustech.edu.cn.

PMID: 35300993
DOI: 10.1016/j.jmb.2022.167536

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-CT², 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.

Keywords: IGF1; IGF1R; conformation change; insulin; ligand-bound states.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Cryoelectron Microscopy
Humans
Insulin* / metabolism
Ligands
Protein Domains
Receptor, IGF Type 1* / chemistry
Receptor, IGF Type 1* / metabolism

Substances

IGF1R protein, human
Insulin
Ligands
Receptor, IGF Type 1