Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain
Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain
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DOI：
10.1126/science.274.5289.948
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发表时间：
1996-11-08
期刊：
影响因子：
56.9
通讯作者：
Pavletich, NP
中科院分区：
文献类型：
--
作者：
Kussie, PH;Gorina, S;Pavletich, NP
MDM2 癌蛋白是 p53 肿瘤抑制因子的细胞抑制剂，因为它可以结合 p53 的反式激活结构域并下调其激活转录的能力。在某些癌症中，MDM2 扩增是一种常见事件，会导致 p53 失活。 MDM2 的 109 个残基氨基末端结构域与 p53 的 15 个残基反式激活结构域肽结合的晶体结构表明，MDM2 具有深疏水性裂缝，p53 肽作为两亲性 α 螺旋结合在该裂缝上。该界面依赖于 MDM2 裂口和 p53 α 螺旋疏水面之间的空间互补性，特别是依赖于插入 MDM2 裂口深处的 p53 氨基酸三联体 - Phe (19)、Trp (23) 和 Leu (26)。这些相同的 p53 残基也参与反式激活，支持 MDM2 通过隐藏其反式激活结构域来灭活 p53 的假设。该结构还表明，两亲性α螺旋可能是多种反式激活因子家族与TATA结合蛋白相关因子结合的常见结构基序。
The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain bf p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic alpha helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of p53 amino acids-Phe(19), Trp(23), and Leu(26)-which insert deep into the MDM2 cleft. these same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic alpha helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.