Bioinformatics Institute (A-STAR), 30 Biopolis Street; #07-01 Matrix, Singapore.
BMC Bioinformatics. 2009 Dec 3;10 Suppl 15(Suppl 15):S6. doi: 10.1186/1471-2105-10-S15-S6.
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.
肿瘤抑制蛋白 p53 受泛素连接酶 MDM2 的调控，后者下调 p53 的水平。在 MDM2 过表达的肿瘤中，可以通过肽或小分子中断 p53-MDM2 相互作用，从而稳定 p53 作为一种治疗策略。结构和生化/突变数据表明，p53 具有 3 个疏水性残基 F19、W23 和 L26，它们嵌入 MDM2 的配体结合口袋中，该口袋具有高度的可塑性，可以调节其大小以适应各种配体。该结合口袋主要依赖于特定残基 Y100 的取向。我们研究了 Y100 动力学在 p53 识别中的作用。
分子动力学模拟表明，Y100 侧链可以处于“打开”或“关闭”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，复合物的形成非常迅速，这是由 p53 的 W23 与 MDM2 的 L54 之间形成氢键或 p53 的 F19 嵌入 MDM2 驱动的。Y100 从“关闭”到“打开”的转变可以增加结合位点的大小。两种状态之间的转换可以由 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 的结合如何通过 Y100 的构象流动性来调节，Y100 是 MDM2 中的门控残基。该残基的流动性可以通过 p53 和 MDM2 的 N 端盖区域的构象来调节。
