Evidence for dynamics in proteins as a mechanism for ligand dissociation.
Evidence for dynamics in proteins as a mechanism for ligand dissociation.
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DOI：
10.1038/nchembio.769
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发表时间：
2012-01-15
影响因子：
14.8
通讯作者：
Lee, Andrew L.
中科院分区：
文献类型：
--
作者：
Carroll, Mary J.;Mauldin, Randall V.;Gromova, Anna V.;Singleton, Scott F.;Collins, Edward J.;Lee, Andrew L.
信号转导、调节过程和药物反应高度依赖于配体的停留时间。洞察物理因素是如何影响停留时间的，应该会增强我们操纵生物相互作用的能力。我们报告了一系列实验，这些实验对二氢叶酸还原酶的八种2，4-二氨基嘧啶抑制剂的KOF进行了结构洞察，这些抑制剂在结合亲和力方面存在六个数量级的差异。核磁共振弛豫色散实验揭示了结合位点附近的一组常见残基，它们经历了协调的毫秒级到以前未知构象的转换事件。从基态构象到激发构象的转换速率与KI和Koff呈指数相关，这表明蛋白质动力学是这一系列中配体解离的机械引发者，并可能对其他大分子-配体系统起作用。尽管Kconf，Forward比Koff快，但配体系列的使用允许在不同时间尺度上的动力学事件之间建立联系。
Signal transduction, regulatory processes, and pharmaceutical responses are highly dependent upon ligand residence times. Gaining insight into how physical factors influence residence times, or koff, should enhance our ability to manipulate biological interactions. We report experiments that yield structural insight into koff for a series of eight 2,4-diaminopyrimidine inhibitors of dihydrofolate reductase that vary by six orders of magnitude in binding affinity. NMR relaxation dispersion experiments revealed a common set of residues near the binding site that undergo a concerted, millisecond-timescale switching event to a previously unidentified conformation. The rate of switching from ground to excited conformations correlates exponentially with Ki and koff, suggesting that protein dynamics serves as a mechanical initiator of ligand dissociation within this series and potentially for other macromolecule-ligand systems. Although kconf,forward is faster than koff, use of the ligand series allowed for connections to be drawn between kinetic events on different timescales.
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