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.
摘要：
2型糖尿病的特征在于胰岛素和胰岛素样生长因子(IGF)信号的破坏。已知这些信号传导级联的关键枢纽-胰岛素受体(IR)和胰岛素样生长因子1受体(IGF1R)-形成胰岛素抗性的功能性IR-IGF1R杂合受体。然而,支撑IR-IGF1R杂化物形成的机制还没有完全理解，阻碍了针对这种受体的未来疗法的调节能力。为了确定合适的干预地点，利用计算热点预测来鉴定用于点诱变靶向的有希望的表位。特定IGF1R点突变F450A,R391A和D555A在基于BRET的供体饱和测定中显示杂合受体的亲和力降低，确认混合形成可以在该界面处进行调制。这些数据为合理设计更有效的杂合受体调节剂提供了基础，支持鉴定与该靶标特异性相互作用的小分子的前景。
