4HBM

Ordering of the N Terminus of Human MDM2 by Small Molecule Inhibitors

4HBM の概要

• エントリーDOI: 10.2210/pdb4hbm/pdb
• 関連するPDBエントリー: 4ERE 4ERF
• 分子名称: E3 ubiquitin-protein ligase Mdm2, {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-1-hydroxybutan-2-yl]-2-oxopiperidin-3-yl}acetic acid (3 entities in total)
• 機能のキーワード: mdm2, p53, protein protein interaction, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 112367.06

構造登録者

Huang, X. (登録日: 2012-09-28, 公開日: 2012-10-17, 最終更新日: 2024-02-28)

主引用文献

Michelsen, K.,Jordan, J.B.,Lewis, J.,Long, A.M.,Yang, E.,Rew, Y.,Zhou, J.,Yakowec, P.,Schnier, P.D.,Huang, X.,Poppe, L.
Ordering of the N-terminus of human MDM2 by small molecule inhibitors.
J.Am.Chem.Soc., 134:17059-17067, 2012

PubMed Abstract: Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel β-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.

PubMed: 22991965
DOI: 10.1021/ja305839b

実験手法

X-RAY DIFFRACTION (1.9 Å)