NDLI: Exploiting Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53

Content Provider	PubMed Central
Author	Joerger, AndreasÂ c. Bauer, MatthiasÂ r. Wilcken, Rainer Baud, MatthiasÂ g. J. Hannes, Harbrecht Exner, ThomasÂ e. Boeckler, FrankÂ m. Spencer, John Fersht, AlanÂ r.
Copyright Year	2015
Abstract	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.
Related Links	http://dx.doi.org/10.1016/j.str.2015.10.016
Ending Page	2255
Page Count	10
Starting Page	2246
File Format	PDF
ISSN	09692126
e-ISSN	18784186
Journal	Structure(London, England:1993)
Issue Number	12
Volume Number	23
Language	English
Publisher	Cell Press
Publisher Date	2015-12-01
Access Restriction	Open
Rights Holder	Cell Press
Subject Keyword	Molecular Biology Structural Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Structural Biology Molecular Biology

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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