光响应分子镊子调节脱氢酶1活性。

IF 3.1 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Antonio L Figueroa Bietti, Alisa-Maite A Kauth, Katrin Hommel, Mike Blueggel, Laurenz Mohr, Felix C Niemeyer, Christine Beuck, Peter Bayer, Shirley K Knauer, Bart Jan Ravoo, Thomas Schrader
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引用次数: 0

摘要

光对蛋白质活性和蛋白质-蛋白质相互作用的精确时空调节起着特殊的刺激作用。在这里,我们介绍了一个光响应的超分子配体系统,旨在调节胱天蛋白酶1,一种对胚胎发生和肿瘤进展至关重要的蛋白酶。我们的方法利用可光开关的二价分子镊子来靶向Taspase 1环内富含赖氨酸的区域。通过加入芳唑吡唑(AAP)光开关,我们实现了配体结合的动态可逆控制。这些光开关具有高的光稳态、优异的可逆性和长时间的Z异构体热稳定性,确保了可靠的开关而不会光降解。镊子距离在E和Z异构体之间变化,从而实现可调的结合相互作用。通过结合表面等离子体共振、酶切实验和分子动力学模拟,我们证明了这些配体以低微摩尔亲和力结合Taspase 1,并有效抑制其蛋白水解活性。虽然异构化对蛋白-蛋白相互作用的抑制作用没有显著影响,但较大的镊子的e -异构体表现出强大的酶抑制作用,可能是由于它们能够桥接活性位点两侧的赖氨酸。这种光开关镊子系统为蛋白质功能的光控调制提供了一种多功能工具,为动态生物环境中选择性靶向富含赖氨酸的蛋白质提供了新的机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Photoresponsive molecular tweezers modulate Taspase 1 activity.

Light serves as an exceptional stimulus for the precise spatiotemporal regulation of protein activity and protein-protein interactions. Here, we introduce a light-responsive supramolecular ligand system designed to modulate Taspase 1, a protease critical for embryogenesis and implicated in tumor progression. Our approach utilizes photoswitchable divalent molecular tweezers engineered to target lysine-rich regions within the Taspase 1 loop. By incorporating arylazopyrazole (AAP) photoswitches, we achieve dynamic and reversible control of ligand binding. These photoswitches exhibit high photostationary states, excellent reversibility, and prolonged thermal stability of the Z isomer, ensuring reliable switching without photodegradation. The tweezer distance varies between E and Z isomers, enabling tunable binding interactions. Through a combination of surface plasmon resonance, enzymatic cleavage assays, and molecular dynamics simulations, we demonstrate that these ligands bind Taspase 1 with low micromolar affinity and effectively inhibit its proteolytic activity. While isomerization did not significantly affect the inhibition of protein-protein interaction, the E-isomers of larger tweezers exhibited powerful enzyme inhibition, likely due to their ability to bridge lysines flanking the active site. This photoswitchable tweezer system provides a versatile tool for light-controlled modulation of protein function, offering new opportunities for selectively targeting lysine-rich proteins in dynamic biological environments.

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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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