Ye Libin, Maji Suvrajit, Sanghera Narinder, Gopalasingam Piraveen, Gorbunov Evgeniy, Tarasov Sergey, Epstein Oleg, Klein-Seetharaman Judith
Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Division of Metabolic and Vascular Health & Systems, Medical School, University of Warwick, Coventry CV4 7AL, UK.
Drug Discov Today. 2017 Jul;22(7):1092-1102. doi: 10.1016/j.drudis.2017.04.011. Epub 2017 May 3.
Recently, major progress has been made in uncovering the mechanisms of how insulin engages its receptor and modulates downstream signal transduction. Here, we present in detail the current structural knowledge surrounding the individual components of the complex, binding sites, and dynamics during the activation process. A novel kinase triggering mechanism, the 'bow-arrow model', is proposed based on current knowledge and computational simulations of this system, in which insulin, after its initial interaction with binding site 1, engages with site 2 between the fibronectin type III (FnIII)-1 and -2 domains, which changes the conformation of FnIII-3 and eventually translates into structural changes across the membrane. This model provides a new perspective on the process of insulin binding to its receptor and, thus, could lead to future novel drug discovery efforts.
最近，在揭示胰岛素与其受体结合并调节下游信号转导的机制方面取得了重大进展。在此，我们详细介绍了围绕该复合物各个组分、结合位点以及激活过程中的动力学的当前结构知识。基于对该系统的现有知识和计算模拟，提出了一种新的激酶触发机制——“弓-箭模型”，其中胰岛素在与结合位点1初始相互作用后，与纤连蛋白III型（FnIII）-1和-2结构域之间的位点2结合，这会改变FnIII-3的构象，并最终转化为跨膜的结构变化。该模型为胰岛素与其受体结合的过程提供了新的视角，因此可能会引领未来新型药物的研发工作。
