148 research outputs found
Structure of the stapled p53 peptide bound to Mdm2
Mdm2 is a major negative regulator of the
tumor suppressor p53 protein, a protein that plays a crucial
role in maintaining genome integrity. Inactivation of p53 is
the most prevalent defect in human cancers. Inhibitors of
the Mdm2
−
p53 interaction that restore the functional p53
constitute potential nongenotoxic anticancer agents with a
novel mode of action. We present here a 2.0 Å resolution
structure of the Mdm2 protein with a bound stapled p53
peptide. Such peptides, which are conformationally and
proteolytically stabilized with all-hydrocarbon staples, are
an emerging class of biologics that are capable of
disrupting protein
−
protein interactions and thus have
broad therapeutic potential. The structure represents the
first crystal structure of an
i
,
i
+ 7 stapled peptide bound to
its target and reveals that rather than acting solely as a
passive conformational brace, a staple can intimately
interact with the surface of a protein and augment the
binding interface
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