Kussie P H, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine A J, Pavletich N P
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Science. 1996 Nov 8;274(5289):948-53. doi: 10.1126/science.274.5289.948.
The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of 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-Phe19, Trp23, and Leu26-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.
MDM2癌蛋白是p53肿瘤抑制因子的一种细胞内抑制剂，因为它能结合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扩增是常见事件，并导致p53失活。与p53的15个残基反式激活结构域肽结合的MDM2的109个残基氨基末端结构域的晶体结构显示，MDM2有一个深的疏水裂缝，p53肽以两亲性α螺旋形式结合在其上。该界面依赖于MDM2裂缝与p53α螺旋疏水表面之间的空间互补性，特别是依赖于p53的三个氨基酸——苯丙氨酸19、色氨酸23和亮氨酸26，它们深深插入MDM2裂缝中。同样这些p53残基也参与反式激活，支持了MDM2通过隐藏其反式激活结构域使p53失活的假说。该结构还表明，两亲性α螺旋可能是多种反式激活因子与TATA结合蛋白相关因子结合中的一种常见结构基序。
