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首页> 外文期刊>Chemistry: A European journal >Site-specific investigation of the steady-state kinetics and dynamics of the multistep binding of bile acid molecules to a lipid carrier protein
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Site-specific investigation of the steady-state kinetics and dynamics of the multistep binding of bile acid molecules to a lipid carrier protein

机译：胆汁酸分子与脂质载体蛋白多步结合的稳态动力学和动力学的定点研究

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摘要

The investigation of multi-site ligand-protein binding and multi-step mechanisms is highly demanding. In this work, advanced NMR methodologies such as 2D H-~(15)N line-shape analysis, which allows a reliable investigation of ligand binding occurring on micro-to millisecond timescales, have been extended to model a two-step binding mechanism. The molecular recognition and complex uptake mechanism of two bile salt molecules by lipid carriers is an interesting example that shows that protein dynamics has the potential to modulate the macromolecule-ligand encounter. Kinetic analysis supports a conformational selection model as the initial recognition process in which the dynamics observed in the apo form is essential for ligand uptake, leading to conformations with improved access to the binding cavity. Subsequent multi-step events could be modelled, for several residues, with a two-step binding mechanism. The protein in the ligand-bound state still exhibits a conformational rearrangement that occurs on a very slow timescale, as observed for other proteins of the family. A global mechanism suggesting how bile acids access the macromolecular cavity is thus proposed.
机译：对多位配体-蛋白质结合和多步机制的研究是非常需要的。在这项工作中，先进的NMR方法学（例如2D H-（15）N线形分析）可以对两步结合机理进行建模，从而可以可靠地研究微秒级到毫秒级发生的配体结合。脂质载体对两个胆汁盐分子的分子识别和复杂摄取机制是一个有趣的例子，表明蛋白质动力学具有调节大分子-配体相遇的潜力。动力学分析支持构象选择模型作为初始识别过程，其中以载脂蛋白形式观察到的动力学对于配体摄取是必不可少的，从而导致构象具有更好的进入结合腔的能力。随后的多步事件可以通过两步绑定机制针对多个残基进行建模。如该家族的其他蛋白质所观察到的，处于配体结合状态的蛋白质仍显示出构象重排，发生在非常缓慢的时间尺度上。因此提出了提示胆汁酸如何进入大分子腔的整体机制。

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