6V4H

Crystal Structure Analysis of Zebra Fish MDMX

6V4H の概要

• エントリーDOI: 10.2210/pdb6v4h/pdb
• 分子名称: Protein Mdm4, Stapled Peptide LSQETF(0EH)DLWKLL(MK8)EN(NH2) (3 entities in total)
• 機能のキーワード: apoptosis, p53 binding
• 由来する生物種: Danio rerio (Zebrafish); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 28060.36

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2019-11-27, 公開日: 2020-04-22, 最終更新日: 2023-11-15)

主引用文献

Ben-Nun, Y.,Seo, H.S.,Harvey, E.P.,Hauseman, Z.J.,Wales, T.E.,Newman, C.E.,Cathcart, A.M.,Engen, J.R.,Dhe-Paganon, S.,Walensky, L.D.
Identification of a Structural Determinant for Selective Targeting of HDMX.
Structure, 28:847-857.e5, 2020

PubMed Abstract: p53 is a critical tumor-suppressor protein that guards the human genome against mutations by inducing cell-cycle arrest or apoptosis. Cancer cells subvert p53 by deletion, mutation, or overexpression of the negative regulators HDM2 and HDMX. For tumors that retain wild-type p53, its reactivation by pharmacologic targeting of HDM2 and/or HDMX represents a promising strategy, with a series of selective small-molecule HDM2 inhibitors and a dual HDM2/HDMX stapled-peptide inhibitor being evaluated in clinical trials. Because selective HDM2 targeting can cause hematologic toxicity, selective HDMX inhibitors could provide an alternative p53-reactivation strategy, but clinical candidates remain elusive. Here, we applied a mutation-scanning approach to uncover p53-based stapled peptides that are selective for HDMX. Crystal structures of stapled-peptide/HDMX complexes revealed a molecular mechanism for the observed specificity, which was validated by HDMX mutagenesis. Thus, we provide a blueprint for the development of HDMX-selective inhibitors to dissect and target the p53/HDMX interaction.

PubMed: 32359398
DOI: 10.1016/j.str.2020.04.011

実験手法

X-RAY DIFFRACTION (1.53 Å)