In Silico Structural Modeling of the HuR-mRNA Complex: Insights into Structural and Functional Regulation.

IF 5.3 2区化学 Q1 CHEMISTRY, MEDICINAL

Journal of Chemical Information and Modeling Pub Date : 2025-10-01 DOI:10.1021/acs.jcim.5c01028

Davide Pietrafesa,Alice Romeo,Fabio Giovanni Tucci,Paola Fiorani,Federico Iacovelli,Mattia Falconi

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引用次数: 0

Abstract

The RNA-binding protein HuR (embryonic lethal abnormal vision-like protein 1) regulates mRNA stability and translation. HuR contains three RNA-recognition motifs (RRMs): the RRM1 and RRM2 confer high-affinity mRNA binding, while RRM3 mediates protein oligomerization. Although HuR is predominantly nuclear, cellular stimuli trigger its cytoplasmic translocation via a nucleocytoplasmic shuttling sequence between the RRM2 and RRM3 domains. Despite HuR's critical role in post-transcriptional gene regulation, its full-length three-dimensional (3D) structure remains uncharacterized. In this study, we employed an in silico approach, combining molecular modeling, atomistic, and coarse-grained molecular dynamics simulations to build and validate a 3D model of the full-length HuR in complex with an mRNA fragment. Structural analysis of the model identified a tyrosine residue as a key mediator of HuR-RNA interaction stability and provided novel structural insights into HuR's RNA-binding mechanism, contributing to a deeper understanding of its regulatory functions.

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HuR-mRNA复合体的计算机结构建模：对结构和功能调控的见解。

rna结合蛋白HuR（胚胎致死性异常视觉样蛋白1）调节mRNA的稳定性和翻译。HuR包含三个rna识别基序（RRMs）： RRM1和RRM2赋予高亲和力的mRNA结合，而RRM3介导蛋白质寡聚化。虽然HuR主要是核的，但细胞刺激通过RRM2和RRM3结构域之间的核胞质穿梭序列触发其细胞质易位。尽管HuR在转录后基因调控中起着关键作用，但其全长三维（3D）结构仍未被表征。在这项研究中，我们采用了一种计算机方法，结合分子建模、原子和粗粒度分子动力学模拟，建立并验证了全长HuR复合物与mRNA片段的3D模型。该模型的结构分析确定了酪氨酸残基作为HuR- rna相互作用稳定性的关键介质，并为HuR的rna结合机制提供了新的结构见解，有助于更深入地了解其调节功能。

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

Journal of Chemical Information and Modeling 化学-化学综合

CiteScore

9.80

自引率

10.70%

发文量

529

审稿时长

1.4 months

期刊介绍： The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.