Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100.
Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100.
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DOI：
10.1186/1471-2105-10-s15-s6
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发表时间：
2009-12-03
影响因子：
3
通讯作者：
Verma CS
中科院分区：
文献类型：
--
作者：
Dastidar SG;Lane DP;Verma CS
肿瘤抑制蛋白p53受泛素连接酶MDM2调控，其下调p53。在MDM2过表达的肿瘤中，p53-MDM2的相互作用可以被肽或小分子打断，以稳定p53作为一种治疗策略。结构和生化/诱变数据表明，p53有3个疏水残基F19、W23和L26嵌入MDM2的配体结合袋中，MDM2具有高度的可塑性，可以调节其大小以容纳多种配体。这个结合袋主要取决于特定残基Y100的取向。我们研究了Y100在p53识别中的动态作用。分子动力学模拟表明，Y100侧链可以处于“开放”或“封闭”状态，只有前者才能形成复合物。当p53和MDM2都处于接近天然构象时，复合物的形成迅速，由p53的W23和MDM2的L54之间形成氢键或p53的F19嵌入MDM2驱动。Y100从“封闭”到“开放”的转变可以增加结合位点的大小。这两种状态之间的相互转换可以由MDM2的n端区域或p53肽的构象诱导。分子动力学模拟揭示了p53与MDM2的结合是如何被MDM2中的看门人残基Y100的构象迁移率调节的。这种残基的迁移可以通过p53的构象和MDM2的末端盖区来调节。
The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. In tumours with overexpressed MDM2, the p53-MDM2 interaction can be interrupted by a peptide or small molecule to stabilize p53 as a therapeutic strategy. Structural and biochemical/mutagenesis data show that p53 has 3 hydrophobic residues F19, W23 and L26 that embed into the ligand binding pocket of MDM2 which is highly plastic in nature and can modulate its size to accommodate a variety of ligands. This binding pocket is primarily dependent on the orientation of a particular residue, Y100. We have studied the role of the dynamics of Y100 in p53 recognition. Molecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states with only the former enabling complex formation. When both p53 and MDM2 are in near native conformations, complex formation is rapid and is driven by the formation of a hydrogen bond between W23 of p53 and L54 of MDM2 or by the embedding of F19 of p53 into MDM2. The transition of Y100 from "closed" to "open" can increase the size of the binding site. Interconversions between these two states can be induced by the N-terminal region of MDM2 or by the conformations of the p53 peptides. Molecular dynamics simulations have revealed how the binding of p53 to MDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2. The mobility of this residue can be modulated by the conformations of p53 and the Nterminal lid region of MDM2.