揭示远端区域在PDK1变构激活中的作用

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nagaraju Mulpuri, Xin-Qiu Yao and Donald Hamelberg*, 
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引用次数: 0

摘要

变构调节是控制多种细胞功能的关键机制。这个过程的关键是一个灵活的生物分子,允许远距离的位点通过协调或顺序的构象变化相互作用。磷酸肌苷依赖性激酶1 (PDK1)具有保守的变张结合位点PIF-pocket,它调节激酶的ATP结合、催化活性和底物相互作用。我们通过比较pif -口袋中与不同小分子变构调节剂结合的激酶与无调节剂的激酶的构象集合来阐明PDK1的变构机制。超过48 μs的模拟分析一致表明,变构调节剂主要影响pif -口袋中特定远端区域的构象动力学,从而驱动变构激活。此外,最近发展的一种先进的差异接触网络社区分析被用于解释变构通信。这种方法将多个构象集成到一个单一的群落网络中,为未来旨在识别蛋白质中功能相关动力学的研究提供了有价值的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Uncovering the Role of Distal Regions in PDK1 Allosteric Activation

Allosteric regulation is a pivotal mechanism governing a wide array of cellular functions. Essential to this process is a flexible biomolecule allowing distant sites to interact through coordinated or sequential conformational shifts. Phosphoinositide-dependent kinase 1 (PDK1) possesses a conserved allosteric binding site, the PIF-pocket, which regulates the kinase’s ATP binding, catalytic activity, and substrate interactions. We elucidated the allosteric mechanisms of PDK1 by comparing conformational ensembles of the kinase bound with different small-molecule allosteric modulators in the PIF-pocket with that of the modulator-free kinase. Analysis of over 48 μs of simulations consistently shows that the allosteric modulators predominantly influence the conformational dynamics of specific distal regions from the PIF-pocket, driving allosteric activation. Furthermore, a recently developed advanced difference contact network community analysis is employed to elucidate allosteric communications. This approach integrates multiple conformational ensembles into a single community network, offering a valuable tool for future studies aimed at identifying function-related dynamics in proteins.

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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
发文量
0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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