Chemical states of the N-terminal "lid" of MDM2 regulate p53 binding Simulations reveal complexities of modulation
Chemical states of the N-terminal "lid" of MDM2 regulate p53 binding Simulations reveal complexities of modulation
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DOI：
10.4161/cc.10.1.14345
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发表时间：
2011-01-01
期刊：
影响因子：
4.3
通讯作者：
Verma, Chandra S.
中科院分区：
文献类型：
--
作者：
Dastidar, Shubhra Ghosh;Raghunathan, Devanathan;Verma, Chandra S.
建议将MDM2(残基1-24)N端“盖子”中的S17磷酸化以调节P53的结合。LID由一个内在无序的多肽基序组成，该基序不能在MDM2 N-末端结构域的晶体结构中分解。MDM2的分子动力学模拟为LID如何根据其磷酸化状态经历复杂的动力学提供了新的见解，而核磁共振分析尚未揭示这一点。磷酸盐和仿磷酸盐‘Asp’之间电荷的差异以及形状从四面体到平面的变化表现为相互作用的强度和持续时间的不同，这些相互作用似乎以不同的方式调节结合部位对配体和肽的访问。这些发现揭示了蛋白质-蛋白质相互作用的复杂性，并协调了生化和核磁共振数据之间的一些差异，表明LID突变或缺失可以改变MDM2的比活性，并为未来评估S17修饰对p53结合的影响提供了概念。
Phosphorylation of S17 in the N-terminal "lid" of MDM2 (residues 1-24) is proposed to regulate the binding of p53. The lid is composed of an intrinsically disordered peptide motif that is not resolved in the crystal structure of the MDM2 N-terminal domain. Molecular dynamics simulations of MDM2 provide novel insights into how the lid undergoes complex dynamics depending on its phosphorylation state that have not been revealed by NMR analyses. The difference in charges between the phosphate and the phosphomimetic 'Asp' and the change in shape from tetrahedral to planar are manifested in differences in strengths and durations of interactions that appear to modulate access of the binding site to ligands and peptides differentially. These findings unveil the complexities that underlie protein-protein interactions and reconcile some differences between the biochemical and NMR data suggesting that lid mutation or deletion can change the specific activity of MDM2 and provide concepts for future approaches to evaluate the effects of S17 modification on p53 binding.