Three STEPs Forward: A Trio of Unexpected Structures of PTPN5.

IF 2.8 4区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Proteins-Structure Function and Bioinformatics Pub Date : 2025-07-05 DOI:10.1002/prot.70013

Liliana Guerrero, Ali Ebrahim, Blake T Riley, Sean H Kim, Anthony C Bishop, Jiaqian Wu, Ye Na Han, Lutz Tautz, Daniel A Keedy

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Abstract

Protein tyrosine phosphatases (PTPs) play pivotal roles in myriad cellular processes by counteracting protein tyrosine kinases. Striatal-enriched protein tyrosine phosphatase (STEP, PTPN5) regulates synaptic function and neuronal plasticity in the brain and is a therapeutic target for several neurological disorders. Here, we present three new crystal structures of STEP, each with unexpected features. These include high-resolution conformational heterogeneity at multiple sites, a highly coordinated citrate molecule in the active site, a previously unseen conformational change at an allosteric site, an intramolecular disulfide bond that was characterized biochemically but had never been visualized structurally, and two serendipitous covalent ligand binding events at surface-exposed cysteines that are nearly or entirely unique to STEP among human PTPs. Together, our results offer new views of the conformational landscape of STEP that may inform structure-based design of allosteric small molecules to specifically inhibit this biomedically important enzyme.

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三步进：PTPN5的三个意外结构。

蛋白酪氨酸磷酸酶（PTPs）通过对抗蛋白酪氨酸激酶在无数细胞过程中发挥关键作用。纹状体富集蛋白酪氨酸磷酸酶（STEP, PTPN5）调节大脑突触功能和神经元可塑性，是几种神经系统疾病的治疗靶点。在这里，我们提出了三种新的STEP晶体结构，每种结构都具有意想不到的特征。其中包括多位点的高分辨率构象异质性，活性位点的高度配位柠檬酸盐分子，变构位点以前未见过的构象变化，分子内二硫键，其生物化学特征但从未在结构上可视化，以及两个偶然的共价配体结合事件在表面暴露的半胱氨酸中几乎或完全是人类PTPs中唯一的STEP。总之，我们的研究结果为STEP的构象景观提供了新的观点，这可能为基于结构的变构小分子设计提供信息，以特异性抑制这种生物医学上重要的酶。

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

Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学

CiteScore

5.90

自引率

3.40%

发文量

172

审稿时长

3 months

期刊介绍： PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.