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Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

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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 Fersht
The 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

Structure

ISSN

0969-2126

Publisher

Elsevier

Issue

12

Volume

23

Page range

2246-2255

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2015-12-02

First Open Access (FOA) Date

2015-12-02

First Compliant Deposit (FCD) Date

2015-12-02

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