PDBsum entry 6v4e

Apoptosis

PDB id: 6v4e

Contents

Protein chains

90 a.a.

15 a.a.

Waters ×121

PDB id:

6v4e

Name:

Apoptosis

Title:

Crystal structure analysis of zebra fish mdm

Structure:

Protein mdm4. Chain: a, b. Synonym: double minute 4 protein,mdm2-like p53-binding protein, protein mdmx,p53-binding protein mdm4. Engineered: yes. Mutation: yes. Stapled peptide qsqqtf(0eh)nlwrll(mk8)qn(nh2). Chain: c, d. Engineered: yes

Source:

Danio rerio. Zebrafish. Organism_taxid: 7955. Gene: mdm4, mdmx. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Organism_taxid: 9606

Resolution:

1.62Å R-factor: 0.162 R-free: 0.199

Authors:

H.-S.Seo,S.Dhe-Paganon

Key ref:

Y.Ben-Nun et al. (2020). Identification of a Structural Determinant for Selective Targeting of HDMX. Structure, 28, 847. PubMed id: 32359398 DOI: 10.1016/j.str.2020.04.011

Date:

27-Nov-19 Release date: 22-Apr-20

Protein chains

Q7ZUW7  (MDM4_DANRE) -  Protein Mdm4 from Danio rerio

Seq: 496 a.a.

Struc: 90 a.a.*

Protein chains

No UniProt id for this chain

Struc: 15 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1016/j.str.2020.04.011

Structure 28:847 (2020)

PubMed id: 32359398

Identification of a Structural Determinant for Selective Targeting of HDMX.

Y.Ben-Nun, H.S.Seo, E.P.Harvey, Z.J.Hauseman, T.E.Wales, C.E.Newman, A.M.Cathcart, J.R.Engen, S.Dhe-Paganon, L.D.Walensky.

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.