The role of dynamic conformational ensembles in biomolecular recognition.
The role of dynamic conformational ensembles in biomolecular recognition.
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DOI：
10.1038/nchembio.232
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发表时间：
2009-11
影响因子：
14.8
通讯作者：
Wright, Peter E.
中科院分区：
文献类型：
--
作者：
Boehr, David D.;Nussinov, Ruth;Wright, Peter E.
分子识别是所有生物过程的核心。在过去的50年里，Koshland的“诱导契合”假说一直是分子识别事件的教科书解释。然而，最近的实验证据支持另一种机制。“构象选择”假设所有蛋白质构象预先存在，并且配体选择最有利的构象。在结合后，系综经历了一个人口转移，重新分配的构象状态。构象选择和诱导适合似乎发挥作用。在通过初级构象选择事件结合之后，侧链和主链相互作用的优化可能通过诱导配合机制进行。已观察到蛋白质-配体、蛋白质-蛋白质、蛋白质-DNA、蛋白质-RNA和RNA-配体相互作用的构象选择。这些数据支持了一种新的分子识别范式，用于疾病中的信号传导、催化、基因调控和蛋白质聚集等过程，这有可能显著影响我们在药物设计、生物分子工程和分子进化方面的观点和策略。
Molecular recognition is central to all biological processes. For the past fifty years, Koshland’s ‘induced fit’ hypothesis has been the textbook explanation for molecular recognition events. However, recent experimental evidence supports an alternative mechanism. ‘Conformational selection’ postulates that all protein conformations pre-exist, and the ligand selects the most favored conformation. Following binding the ensemble undergoes a population shift, redistributing the conformational states. Both conformational selection and induced fit appear to play roles. Following binding by a primary conformational selection event, optimization of side-chain and backbone interactions is likely to proceed by an induced fit mechanism. Conformational selection has been observed for protein-ligand, protein-protein, protein-DNA, protein-RNA and RNA-ligand interactions. These data support a new molecular recognition paradigm for processes as diverse as signaling, catalysis, gene regulation, and protein aggregation in disease, which has the potential to significantly impact our views and strategies in drug design, biomolecular engineering and molecular evolution.
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