Using site-directed mutagenesis to further the understanding of insulin receptor-insulin like growth factor-1 receptor heterodimer structure

IF 1.6 4区 医学 Q4 CELL BIOLOGY Growth Hormone & Igf Research Pub Date : 2024-07-18 DOI:10.1016/j.ghir.2024.101607
Samuel Turvey , Stephen P. Muench , Tarik Issad , Colin W.G. Fishwick , Mark T. Kearney , Katie J. Simmons
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Abstract

Type 2 diabetes is characterised by the disruption of insulin and insulin-like growth factor (IGF) signalling. The key hubs of these signalling cascades - the Insulin receptor (IR) and Insulin-like growth factor 1 receptor (IGF1R) – are known to form functional IR-IGF1R hybrid receptors which are insulin resistant. However, the mechanisms underpinning IR-IGF1R hybrid formation are not fully understood, hindering the ability to modulate this for future therapies targeting this receptor. To pinpoint suitable sites for intervention, computational hotspot prediction was utilised to identify promising epitopes for targeting with point mutagenesis. Specific IGF1R point mutations F450A, R391A and D555A show reduced affinity of the hybrid receptor in a BRET based donor-saturation assay, confirming hybrid formation could be modulated at this interface. These data provide the basis for rational design of more effective hybrid receptor modulators, supporting the prospect of identifying a small molecule that specifically interacts with this target.

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利用定点突变进一步了解胰岛素受体-胰岛素样生长因子-1 受体异二聚体的结构
2 型糖尿病的特点是胰岛素和胰岛素样生长因子 (IGF) 信号的中断。众所周知,这些信号级联的关键枢纽--胰岛素受体(IR)和胰岛素样生长因子1受体(IGF1R)--会形成功能性的IR-IGF1R混合受体,从而对胰岛素产生抵抗。然而,IR-IGF1R 杂交受体的形成机制尚未完全明了,这阻碍了未来针对该受体的疗法对其进行调节的能力。为了确定合适的干预位点,研究人员利用计算热点预测来确定有希望的表位,以便利用点突变技术进行靶向治疗。特定的 IGF1R 点突变 F450A、R391A 和 D555A 在基于 BRET 的供体饱和试验中显示出混合受体的亲和力降低,这证实了混合体的形成可以在这个界面上进行调节。这些数据为合理设计更有效的杂交受体调节剂提供了基础,支持了发现能与这一靶点特异性相互作用的小分子的前景。
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来源期刊
Growth Hormone & Igf Research
Growth Hormone & Igf Research 医学-内分泌学与代谢
CiteScore
3.30
自引率
0.00%
发文量
38
审稿时长
57 days
期刊介绍: Growth Hormone & IGF Research is a forum for research on the regulation of growth and metabolism in humans, animals, tissues and cells. It publishes articles on all aspects of growth-promoting and growth-inhibiting hormones and factors, with particular emphasis on insulin-like growth factors (IGFs) and growth hormone. This reflects the increasing importance of growth hormone and IGFs in clinical medicine and in the treatment of diseases.
期刊最新文献
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