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

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53
Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53
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
0969-2126
2246-2255
Joerger, Andreas C.
69e42747-d541-4f47-92e5-d8ddd7d73c27
Bauer, Matthias R.
606d5d28-6086-4988-89b5-fa07d3619022
Wilcken, Rainer
54a2bb56-c547-477b-bdda-141de61ca08c
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Harbrecht, Hannes
e15c7ed0-329c-4bc7-a63f-f931196ede77
Exner, Thomas E.
8fff443e-12c5-404e-862c-b1651ac4973b
Boeckler, Frank M.
d137746c-22ff-49db-8177-051e246ce7d6
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
Fersht, Alan R.
b5145a83-e9cb-426f-8722-f60eb9aa59a5
Joerger, Andreas C.
69e42747-d541-4f47-92e5-d8ddd7d73c27
Bauer, Matthias R.
606d5d28-6086-4988-89b5-fa07d3619022
Wilcken, Rainer
54a2bb56-c547-477b-bdda-141de61ca08c
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Harbrecht, Hannes
e15c7ed0-329c-4bc7-a63f-f931196ede77
Exner, Thomas E.
8fff443e-12c5-404e-862c-b1651ac4973b
Boeckler, Frank M.
d137746c-22ff-49db-8177-051e246ce7d6
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
Fersht, Alan R.
b5145a83-e9cb-426f-8722-f60eb9aa59a5

Joerger, Andreas C., Bauer, Matthias R., Wilcken, Rainer, Baud, Matthias, Harbrecht, Hannes, Exner, Thomas E., Boeckler, Frank M., Spencer, John and Fersht, Alan R. (2015) Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53. Structure, 23 (12), 2246-2255. (doi:10.1016/j.str.2015.10.016). (PMID:26636255)

Record type: Article

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

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Accepted/In Press date: October 2015
Published date: 1 December 2015

Identifiers

Local EPrints ID: 400499
URI: http://eprints.soton.ac.uk/id/eprint/400499
ISSN: 0969-2126
PURE UUID: 6f160daa-83f0-42aa-91fb-11a5cd0bc9d3
ORCID for Matthias Baud: ORCID iD orcid.org/0000-0003-3714-4350

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Date deposited: 16 Sep 2016 14:34
Last modified: 15 Mar 2024 03:54

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Contributors

Author: Andreas C. Joerger
Author: Matthias R. Bauer
Author: Rainer Wilcken
Author: Matthias Baud ORCID iD
Author: Hannes Harbrecht
Author: Thomas E. Exner
Author: Frank M. Boeckler
Author: John Spencer
Author: Alan R. Fersht

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