Journal article
Activation of the human insulin receptor by non-insulin-related peptides
NS Kirk, Q Chen, YG Wu, AL Asante, H Hu, JF Espinosa, F Martínez-Olid, MB Margetts, FA Mohammed, VV Kiselyov, DG Barrett, MC Lawrence
Nature Communications | NATURE PORTFOLIO | Published : 2022
Abstract
The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helica..
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Awarded by Eli Lilly and Company
Funding Acknowledgements
All work undertaken at WEHI byM. C.L., N.S.K. andM.B. M. was funded by a Research Agreement from Eli Lilly and Company (Indianapolis). WEHI receives Victorian State Government Operational Infrastructure Support and funding from the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme. The authors acknowledge the use of instruments at the Monash Ramaciotti Centre for Cryo-Electron Microscopy (a Node of Microscopy Australia) and the use of associated equipment funded by the Australian Research Council grant LE120100090 and thank Hari Venugopal (Monash University) for his as Fce in this regard. Part of the NMR data analysis was carried out under contract to SaRomics (Lund, Sweden) and we thank Carl Diehl (SaRomics) for his contribution in this regard. We also thank Julia Cummins and Wayne Hohn (Eli Lilly and Co.) for peptide preparation, and Prof. Ken Siddle (University of Cambridge) for the provision of the hybridoma expressing the monoclonal antibody mAb 83-7.