5MNJ

Structure of MDM2-MDMX-UbcH5B-ubiquitin complex

5MNJ の概要

• エントリーDOI: 10.2210/pdb5mnj/pdb
• 分子名称: Ubiquitin-conjugating enzyme E2 D2, Polyubiquitin-B, E3 ubiquitin-protein ligase Mdm2, ... (7 entities in total)
• 機能のキーワード: ubiquitin ligase, ligase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 86014.67

構造登録者

Klejnot, M.,Huang, D.T. (登録日: 2016-12-13, 公開日: 2017-05-31, 最終更新日: 2024-01-17)

主引用文献

Nomura, K.,Klejnot, M.,Kowalczyk, D.,Hock, A.K.,Sibbet, G.J.,Vousden, K.H.,Huang, D.T.
Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity.
Nat. Struct. Mol. Biol., 24:578-587, 2017

PubMed Abstract: MDM2-MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2-MDMX-E2(UbcH5B)-ubiquitin complex, we designed MDM2 mutants that prevent E2-ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53's transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors.

PubMed: 28553961
DOI: 10.1038/nsmb.3414

実験手法

X-RAY DIFFRACTION (2.16 Å)