6V4F

Crystal Structure Analysis of Zebra Fish MDMX

Summary for 6V4F

• Entry DOI: 10.2210/pdb6v4f/pdb
• Descriptor: Protein Mdm4, Stapled Peptide LSQETF(0EH)DLWKLE(MK8)EN(NH2), SULFATE ION, ... (4 entities in total)
• Functional Keywords: apoptosis, p53 binding
• Biological source: Danio rerio (Zebrafish); More
• Total number of polymer chains: 2
• Total formula weight: 14273.40

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2019-11-27, release date: 2020-04-22, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.35 Å)