Kaye Samantha L, Sansom Mark S P, Biggin Philip C
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
J Biol Chem. 2006 May 5;281(18):12736-42. doi: 10.1074/jbc.M512728200. Epub 2006 Mar 2.
The mechanism of partial agonism at N-methyl-D-aspartate receptors is an unresolved issue, especially with respect to the role of protein dynamics. We have performed multiple molecular dynamics simulations (7 x 20 ns) to examine the behavior of the ligand-binding core of the NR1 subunit with a series of ligands. Our results show that water plays an important role in stabilizing different conformations of the core and how a closed cleft conformation of the protein might be stabilized in the absence of ligands. In the case of ligand-bound simulations with both full and partial agonists, we observed that ligands within the binding cleft may undergo distinct conformational changes, without grossly influencing the degree of cleft closure within the ligand-binding domain. In agreement with recently published crystallographic data, we also observe similar changes in backbone torsions corresponding to the hinge region between the two lobes for the partial agonist, D-cycloserine. This observation rationalizes the classification of D-cycloserine as a partial agonist and should provide a basis with which to predict partial agonism in this class of receptor by analyzing the behavior of these torsions with other potential ligands.
N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptors）上部分激动作用的机制是一个尚未解决的问题，尤其是在蛋白质动力学的作用方面。我们进行了多次分子动力学模拟（7×20纳秒），以研究NR1亚基的配体结合核心与一系列配体的行为。我们的结果表明，水在稳定核心的不同构象以及在没有配体的情况下蛋白质的闭合裂隙构象如何被稳定方面起着重要作用。在使用完全激动剂和部分激动剂进行配体结合模拟的情况下，我们观察到结合裂隙内的配体可能会经历不同的构象变化，而不会严重影响配体结合域内裂隙闭合的程度。与最近发表的晶体学数据一致，我们还观察到部分激动剂D-环丝氨酸（D-cycloserine）对应于两个叶之间铰链区域的主链扭转有类似变化。这一观察结果使D-环丝氨酸作为部分激动剂的分类合理化，并应为通过分析这些扭转与其他潜在配体的行为来预测这类受体中的部分激动作用提供基础。
