Identification of a Structural Determinant for Selective Targeting of HDMX.

Publication Type:

Journal Article


Structure, Volume 28, Issue 7, p.847-857.e5 (2020)


<p>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.</p>

1.62Å (PDB: 6V4E; SAH-p53-8/zHDMX), 1.25Å (PDB: 6V4G, SAH-p53-8 L26E/zHDMX), 1.53Å (PDB: 6V4H; SAH-p53-4/zHDMX), and 1.35Å (PDB: 6V4F; SAH-p53-4/zHDMX L26E).