The inositol 1,4,5-triphosphate receptor (IPR) mediates Ca release in many cell types and is pivotal to a wide range of cellular processes. High-resolution cryoelectron microscopy studies have provided new structural details of IPR type 1 (IPR1), showing that channel function is determined by the movement of various domains within and between each of its four subunits. Channel properties are regulated by ligands, such as Ca and IP3, which bind at specific sites and control the interactions between these domains. However, it is not known how the various ligand-binding sites on IPR1 interact to control the opening of the channel. In this study, we present a coarse-grained model of IPR1 that accounts for the channel architecture and the location of specific Ca- and IP3-binding sites. This computational model accounts for the domain-domain interactions within and between the four subunits that form IPR1, and it also describes how ligand binding regulates these interactions. Using a kinetic model, we explore how two Ca-binding sites on the cytosolic side of the channel interact with the IP3-binding site to regulate the channel open probability. Our primary finding is that the bell-shaped open probability of IPR1 provides constraints on the relative strength of these regulatory binding sites. In particular, we argue that a specific Ca-binding site, whose function has not yet been established, is very likely a channel antagonist. Additionally, we apply our model to show that domain-domain interactions between neighboring subunits exert control over channel cooperativity and dictate the nonlinear response of the channel to Ca concentration. This suggests that specific domain-domain interactions play a pivotal role in maintaining the channel’s stability, and a disruption of these interactions may underlie disease states associated with Ca dysregulation.

中文翻译：

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结合 Ca 和 IP3 调节的 IP3R1 基于结构的计算模型

肌醇 1,4,5-三磷酸受体 (IPR) 介导许多细胞类型中的 Ca 释放，并且对于多种细胞过程至关重要。高分辨率冷冻电子显微镜研究提供了 IPR 1 型 (IPR1) 的新结构细节，表明通道功能是由其四个亚基内部和之间的各个域的运动决定的。通道特性由配体调节，例如 Ca 和 IP3，它们结合在特定位点并控制这些结构域之间的相互作用。然而，尚不清楚 IPR1 上的各种配体结合位点如何相互作用来控制通道的打开。在这项研究中，我们提出了 IPR1 的粗粒度模型，该模型解释了通道结构以及特定 Ca 和 IP3 结合位点的位置。该计算模型解释了形成 IPR1 的四个亚基内部和之间的域-域相互作用，并且还描述了配体结合如何调节这些相互作用。使用动力学模型，我们探讨了通道胞质侧的两个 Ca 结合位点如何与 IP3 结合位点相互作用以调节通道开放概率。我们的主要发现是 IPR1 的钟形开放概率对这些调控结合位点的相对强度提供了限制。特别是，我们认为特定的 Ca 结合位点（其功能尚未确定）很可能是通道拮抗剂。此外，我们应用我们的模型来表明相邻亚基之间的域-域相互作用对通道协同性进行控制，并决定通道对 Ca 浓度的非线性响应。这表明特定的域-域相互作用在维持通道的稳定性方面发挥着关键作用，并且这些相互作用的破坏可能是与 Ca 失调相关的疾病状态的基础。