Structural details on mdm2-p53 interaction = mdm2 와 p53 간의 상호작용에 대한 구조분석

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Structural details on mdm2-p53 interaction = mdm2 와 p53 간의 상호작용에 대한 구조분석
Seung-Wook Chi; Si-Hyung Lee; Do-Hyoung Kim; Min Jung Ahn; Jae Sung Kim; Jin Young Woo; T Torizawa; M Kainosho; Kyou Hoon Han
Bibliographic Citation
Journal of Biological Chemistry, vol. 280, no. 46, pp. 38795-38802
Publication Year
Mdm2 is a cellular antagonist of p53 that keeps a balanced cellular level of p53. The two proteins are linked by a negative regulatory feedback loop and physically bind to each other via a putative helix formed by residues 18-26 of p53 transactivation domain (TAD) and its binding pocket located within the N-terminal 100-residue domain of mdm2 (Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., and Pavletich, N. P. (1996) Science 274, 948-953). In a previous report we demonstrated that p53 TAD in the mdm2-freee state is mostly unstructured but contains two nascent turns in addition to a preformed" helix that is the same as the putative helix mediating p53-mdm2 binding. Here, using heteronuclear multidimensional NMR methods, we show that the two nascent turn motifs in p53 TAD, turn I (residues 40-45) and turn II (residues 49-54), are also capable of binding to mdm2. In particular, the turn II motif has a higher mdm2 binding affinity (∼20 μM) than the turn I and targets the same site in mdm2 as the helix. Upon mdm2 binding this motif becomes a well defined full helix turn whose hydrophobic face formed by the side chains of Ile-50, Trp-53, and Phe-54 inserts deeply into the helix binding pocket. Our results suggest that p53-mdm2 binding is subtler than previously thought and involves global contacts such as multiple "non-contiguous" minimally structured motifs instead of being localized to one small helix mini-domain in p53 TAD.
Amer Soc Biochemistry Molecular Biology Inc
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Division of Biomedical Research > 1. Journal Articles
Division of Bio Technology Innovation > Core Research Facility & Analysis Center > 1. Journal Articles
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