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Structural basis for the conformational changes of insulin receptor induced by three different hormone ligands

This article is a preprint and has not been certified by peer review.

Authors

    Xi Zhang,  
    Xi Zhang
    • Southern University of Science and Technology
    Ting Zhang,  
    Ting Zhang
    Cang Wu,  
    Cang Wu
    • Southern University of Science and Technology
    Yuanzhu Gao,  
    Yuanzhu Gao
    • Southern University of Science and Technology
    Shuo Zhang,  
    Shuo Zhang
    • Zhengzhou University
    Zhenglin Li,   Linshan Zhong,   Chenyu Xia,   Liuqing Yang,   Fengquan Dong,   Qing Shu,  
    Qing Shu
    • Shenzhen People's Second Hospital
    Yang Fu,  
    Yang Fu
    Renhong Yan
    Renhong Yan
Categories
Biochemistry & Biophysics
Keywords
Insulin receptor; IGF-I; IGF-II; Cryo-electron microscopy

Abstract

The insulin receptor (IR) is central to the regulation of glucose and lipid metabolism. Although insulin is its primary ligand, insulin-like growth factors I and II (IGF-I and IGF-II) also engage IR, albeit with reduced affinity. The structural basis of cooperative ligand binding, however, has remained poorly understood. Here, we report cryo-Electron Microscopy (cryo-EM) structures of IR in complex with insulin, IGF-I, and IGF-II, revealing that all three ligands engage the receptor at overlapping binding sites and can induce a conserved T-shaped quaternary assembly involving four ligand molecules at site 1/1′ and site 2/2′. Despite this shared overall architecture, distinct ligand-specific conformational changes were observed. Notably, IGF-I and IGF-II adopt different binding sequence at site 1 and site 2 compared to insulin, suggesting unique interaction dynamics. These structural insights highlight divergent mechanisms of ligand recognition and cooperative binding, providing a deeper understanding of hormone-induced conformational modulation of the IR.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.01.19.000091

Submission ID:

91

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Posted

2026-01-19

How to Cite

Zhang, X., Zhang, T., Wu, C., Gao, Y., Zhang, S., Li, Z., Zhong, L., Xia, C., Yang, L., Dong, F., Shu, Q., Fu, Y., & Yan, R. (2026). Structural basis for the conformational changes of insulin receptor induced by three different hormone ligands. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.01.19.000091

Declaration of Competing Interests

The authors declare no competing interests to disclose.

Copyright

The copyright holder for this preprint is the author/funder.

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.