structure with andreas final.pdf (3.1 MB)
Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53
journal contribution
posted on 2023-06-08, 23:36 authored by Andreas C Joerger, Matthias R Bauer, Rainer Wilcken, Matthias G J Baud, Hannes Harbrecht, Thomas E Exner, Frank M Boeckler, John SpencerJohn Spencer, Alan R FershtThe destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process.
Funding
Rescuing Thermally Unstable p53 Mutants with Small Molecules; New Targeted Cancer Therapies.; G1388; ASSOCIATION FOR INTERNATIONAL CANCER RESEARCH; 14-1002
History
Publication status
- Published
File Version
- Published version
Journal
StructureISSN
0969-2126Publisher
ElsevierExternal DOI
Issue
12Volume
23Page range
2246-2255Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2015-12-02First Open Access (FOA) Date
2015-12-02First Compliant Deposit (FCD) Date
2015-12-02Usage metrics
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