High-resolution double vision of the allosteric phosphatase PTP1B.
High-resolution double vision of the allosteric phosphatase PTP1B.
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DOI：
10.1107/s2053230x23010749
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发表时间：
2024-01-01
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高分辨率X射线晶体学揭示了动态酶PTP1B构象异质性的新细节。蛋白酪氨酸磷酸酶1B（PTP1B）在细胞内稳态中起着重要作用，是多种人类疾病（包括糖尿病、肥胖和乳腺癌）的高度有效的治疗靶点。然而，关于构象变化如何通过PTP1B的结构传递信息，以使配体或对突变的功能反应能够进行变构调节，还有很多东西有待了解。高分辨率X射线晶体学可以为蛋白质构象集合提供独特的窗口，但即使是高分辨率结构的比较也往往会因数据集之间的差异而变得复杂，包括非同构。在这里，在PDB中总共10350个PTP1B结构中，呈现了迄今为止载脂蛋白野生型（WT）PTP1B的最高分辨率晶体结构。这种结构是一种晶体形式，这是罕见的PTP1B，具有两个独特的拷贝的蛋白质，表现出不同的模式的构象异质性，允许控制比较的局部障碍，在同一个不对称单元内的两条链。这些链之间的构象差异在载脂蛋白结构和最近报道的几个高分辨率配体结合结构之间进行了询问。最近报道的激活双突变体的高分辨率结构中的电子密度图也进行了检查，发现突变体结构中未建模的替代构象与新WT结构中构象异质性增强的区域相一致。这些结果验证了这些突变通过增强局部动力学而起作用的概念，并表明WT酶对这种变化具有潜在的易感性。总之，这些新的数据和分析提供了PTP1B构象集合的详细视图，并强调了高分辨率晶体学用于阐明构象异质性与功能潜在相关性的实用性。
High-resolution X-ray crystallography reveals new details of conformational heterogeneity for the dynamic enzyme PTP1B. Protein tyrosine phosphatase 1B (PTP1B) plays important roles in cellular homeostasis and is a highly validated therapeutic target for multiple human ailments, including diabetes, obesity and breast cancer. However, much remains to be learned about how conformational changes may convey information through the structure of PTP1B to enable allosteric regulation by ligands or functional responses to mutations. High-resolution X-ray crystallography can offer unique windows into protein conformational ensembles, but comparison of even high-resolution structures is often complicated by differences between data sets, including non-isomorphism. Here, the highest resolution crystal structure of apo wild-type (WT) PTP1B to date is presented out of a total of ∼350 PTP1B structures in the PDB. This structure is in a crystal form that is rare for PTP1B, with two unique copies of the protein that exhibit distinct patterns of conformational heterogeneity, allowing a controlled comparison of local disorder across the two chains within the same asymmetric unit. The conformational differences between these chains are interrogated in the apo structure and between several recently reported high-resolution ligand-bound structures. Electron-density maps in a high-resolution structure of a recently reported activating double mutant are also examined, and unmodeled alternate conformations in the mutant structure are discovered that coincide with regions of enhanced conformational heterogeneity in the new WT structure. These results validate the notion that these mutations operate by enhancing local dynamics, and suggest a latent susceptibility to such changes in the WT enzyme. Together, these new data and analysis provide a detailed view of the conformational ensemble of PTP1B and highlight the utility of high-resolution crystallography for elucidating conformational heterogeneity with potential relevance for function.
影响因子：
5.9
作者：
Morris, Rhiannon;Keating, Narelle;Tan, Cyrus;Chen, Hao;Laktyushin, Artem;Saiyed, Tamanna;Liau, Nicholas P. D.;Nicola, Nicos A.;Tiganis, Tony;Kershaw, Nadia J.;Babon, Jeffrey J.
通讯作者：
Babon, Jeffrey J.