Conformational footprints of agonism: Differences of inositol 1,4,5-trisphosphate (IP₃) and adenophostin A on IP₃ receptor’s N-terminal dynamics

Inositol 1,4,5-trisphosphate receptor (IP3R) represents a major family of intracellular Ca2+-release channel. Distal to its pore-forming region lies its cytoplasmic N-terminus (NT) that harbours the agonist-binding pocket. Although inositol 1,4,5-trisphosphate (IP3) is the endogenous agonist, the fungal metabolite adenophostin A (AdA) is known to function as a “super-agonist”, displaying roughly ten-fold higher affinity on binding. Using all-atom molecular dynamics simulations of rat IP3R1 NT in apo, IP3-bound and AdA-bound states, we here show that both agonists alter NT’s flexibility, yet principal component analysis reveals that AdA drives the domain into broader and distinct conformational substates that are visited by neither the apo nor the IP3-bound form. AdA occupies a more spacious, hydrophobic pocket, engaging a wider spectrum of transient polar and non-polar contacts and favouring an entropy-dominated binding mode despite fewer enduring hydrogen bonds. Dynamic cross-correlati..., , # Conformational footprints of agonism: Differences of inositol 1,4,5-trisphosphate (IP~3~) and adenophostin A on IP~3~ receptor’s N-terminal dynamics Dataset DOI: [10.5061/dryad.98sf7m0wp](10.5061/dryad.98sf7m0wp) ## Overview This dataset contains molecular dynamics (MD) simulation outputs and Boltz-2 structure prediction outputs used to investigate the structural dynamics and ligand binding of the IP3 receptor N-terminal region in three states: * apo (unbound) * IP3-bound * adenophostin A (AdA)-bound The MD data include reference structures and simulation trajectories. The Boltz-2 data include predicted structures, affinity outputs, confidence summaries, and model confidence/error files. ## File structure ### `data.zip` Compressed archive containing the following folders: * `MD_data/` * `boltz_data/` --- ## `MD_data/` This folder contains structures and trajectories for the apo, IP3-bound, and AdA-bound systems. ### Reference structure files * `apo.pdb` * `IP3_bound.pdb`..., ,肌醇1,4,5-三磷酸受体（inositol 1,4,5-trisphosphate receptor, IP3R）是一类主要的细胞内钙离子释放通道家族。其孔形成区域的远端存在胞质N端结构域（N-terminus, NT），该结构域包含激动剂结合口袋。尽管肌醇1,4,5-三磷酸（inositol 1,4,5-trisphosphate, IP3）是内源性激动剂，但真菌代谢产物腺苷酸菌素A（adenophostin A, AdA）被证实为‘超级激动剂’，其结合亲和力约为IP3的10倍。本研究针对大鼠IP3R1 NT的未结合配体（apo）、IP3结合态及AdA结合态体系开展全原子分子动力学模拟，结果显示两类激动剂均会改变NT的柔性，但主成分分析表明，AdA可诱导该结构域形成更宽泛且独特的构象亚状态，此类构象既未在apo态也未在IP3结合态中被观测到。AdA占据更为宽敞的疏水口袋，可形成更广泛的瞬时极性与非极性相互作用；尽管其持久氢键数量更少，但更倾向于以熵主导的结合模式。动态互相关... # 激动剂的构象特征：肌醇1,4,5-三磷酸（IP3）与腺苷酸菌素A（AdA）对IP3受体N端动态特性的差异影响 数据集DOI：[10.5061/dryad.98sf7m0wp] ## 概述 本数据集包含分子动力学（molecular dynamics, MD）模拟输出结果与Boltz-2结构预测输出结果，用于探究IP3受体N端区域在三种状态下的结构动态与配体结合特性： * 未结合配体（apo）态 * IP3结合态 * 腺苷酸菌素A（AdA）结合态 MD数据包含参考结构与模拟轨迹。Boltz-2数据包含预测结构、亲和力输出结果、置信度汇总文件以及模型置信度/误差文件。 ## 文件结构 ### `data.zip` 包含以下文件夹的压缩归档： * `MD_data/` * `boltz_data/` --- ## `MD_data/` 该文件夹包含未结合配体、IP3结合及AdA结合体系的结构文件与模拟轨迹。 ### 参考结构文件 * `apo.pdb` * `IP3_bound.pdb`...