 |
PDBsum entry 6v4e
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Identification of a structural determinant for selective targeting of hdmx.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
Structure, 2020,
28,
847.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
