Enzyme kinetics model for the coronavirus main protease including dimerization and ligand binding.

IF 3.2 3区 生物学 Q2 BIOPHYSICS
Van N T La, Lulu Kang, David D L Minh
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引用次数: 0

Abstract

The coronavirus main protease (MPro) plays a pivotal role in viral replication and is the target of several antivirals against SARS-CoV-2. In some species, CRCs of MPro enzymatic activity can exhibit biphasic behavior in which low ligand concentrations activate the enzyme whereas higher ones inhibit it. While this behavior has been attributed to ligand-induced dimerization, quantitative enzyme kinetics models have not been fit to it. Here, we develop a kinetic model integrating dimerization and ligand binding. We perform a Bayesian regression to globally fit the model to multiple types of biochemical and biophysical data. The reversible covalent inhibitor GC376 strongly induces dimerization and binds to the dimer with no cooperativity. In contrast, the fluorescent peptide substrate has a minor effect on dimerization but binds to the dimer with positive cooperativity. The biphasic concentration response curve occurs because compared to substrate, the inhibitor accelerates turnover in the opposite catalytic site.

冠状病毒主要蛋白酶的酶动力学模型,包括二聚化和配体结合。
冠状病毒主要蛋白酶(MPro)在病毒复制中起着关键作用,是几种抗病毒药物对抗SARS-CoV-2的靶点。在某些物种中,具有MPro酶活性的CRCs可以表现出双相行为,即低配体浓度激活酶,而高配体浓度则抑制酶。虽然这种行为归因于配体诱导的二聚化,但定量酶动力学模型并不适合它。在这里,我们建立了一个整合二聚化和配体结合的动力学模型。我们执行贝叶斯回归全局拟合模型多种类型的生化和生物物理数据。可逆共价抑制剂GC376强烈诱导二聚体,与二聚体无协同作用。相比之下,荧光肽底物对二聚体的影响较小,但与二聚体结合具有正协同性。出现双相浓度响应曲线是因为与底物相比,抑制剂加速了相反催化位点的转化。
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
Biophysical journal
Biophysical journal 生物-生物物理
CiteScore
6.10
自引率
5.90%
发文量
3090
审稿时长
2 months
期刊介绍: BJ publishes original articles, letters, and perspectives on important problems in modern biophysics. The papers should be written so as to be of interest to a broad community of biophysicists. BJ welcomes experimental studies that employ quantitative physical approaches for the study of biological systems, including or spanning scales from molecule to whole organism. Experimental studies of a purely descriptive or phenomenological nature, with no theoretical or mechanistic underpinning, are not appropriate for publication in BJ. Theoretical studies should offer new insights into the understanding ofexperimental results or suggest new experimentally testable hypotheses. Articles reporting significant methodological or technological advances, which have potential to open new areas of biophysical investigation, are also suitable for publication in BJ. Papers describing improvements in accuracy or speed of existing methods or extra detail within methods described previously are not suitable for BJ.
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