Exploring insulin-receptor dynamics: Stability and binding mechanisms

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2025-05-26 DOI:10.1016/j.str.2025.04.022

Amanda D. Stange, Lorena Zuzic, Birgit Schiøtt, Nils A. Berglund

引用次数: 0

Abstract

Insulin binding to the insulin receptor (IR) induces large conformational changes leading to receptor activation. Although there exists a considerable number of IR structures in different conformational and insulin-saturation states, they cannot provide dynamic information or the resolved order of events leading to receptor activation. In this study, we employed molecular dynamics (MD) simulations to the experimentally solved structures of IR-insulin complexes occurring under physiological concentration conditions. We observed that insulin bound to the hybrid sites induced opening of site 1, and that site 1-bound insulin contributed to the extension of the α helix in the C terminus of the α chain (αCT) and increased inter-domain stabilization. Many models have previously been proposed for the activation of IR. Based on our observations, we propose a novel “ladder-climbing” mechanism of insulin-induced IR activation, where insulin gradually migrates from site 2 to site 1 while inducing a controlled conformational change in IR.

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探索胰岛素受体动力学：稳定性和结合机制

胰岛素结合到胰岛素受体（IR）诱导大构象变化导致受体激活。虽然存在相当数量的不同构象和胰岛素饱和状态的IR结构，但它们不能提供动态信息或导致受体激活的事件的确定顺序。在这项研究中，我们采用分子动力学（MD）模拟实验解决了生理浓度条件下ir -胰岛素复合物的结构。我们观察到胰岛素结合到杂交位点诱导位点1的开放，并且位点1结合的胰岛素有助于α链C端α螺旋的延伸（α ct）和增强结构域间的稳定性。以前已经提出了许多IR激活的模型。基于我们的观察，我们提出了胰岛素诱导IR激活的一种新的“阶梯攀登”机制，胰岛素逐渐从位点2迁移到位点1，同时诱导IR的受控构象变化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.