Identification of a druggable protein-protein interaction site between mutant p53 and its stabilizing chaperone DNAJA1.

The Journal of Biological Chemistry
Xin TongGuang-Yu Yang

Abstract

The TP53 gene is the most frequently mutated gene in human cancers, and the majority of TP53 mutations are missense mutations. As a result, these mutant p53 (mutp53) either directly lose wildtype p53 (wtp53) tumor suppressor function or exhibit a dominant negative effect over wtp53. In addition, some mutp53 have acquired new oncogenic function (gain of function). Therefore, targeting mutp53 for its degradation may serve as a promising strategy for cancer prevention and therapy. Based on our previous finding that farnesylated DNAJA1 is a crucial chaperone in maintaining mutp53 stabilization, and by using an in silico approach, we built 3D homology models of human DNAJA1 and mutp53R175H proteins, identified the interacting pocket in the DNAJA1-mutp53R175H complex, and found one critical druggable small molecule binding site in the DNAJA1 glycine/phenylalanine-rich region. We confirmed that the interacting pocket in the DNAJA1-mutp53R175H complex was crucial for stabilizing mutp53R175H using a site-directed mutagenesis approach. We further screened a drug-like library to identify a promising small molecule hit (GY1-22) against the interacting pocket in the DNAJA1-mutp53R175H complex. The GY1-22 compound displayed an effective acti...Continue Reading

References

May 15, 1997·Nature·M H KubbutatK H Vousden
Aug 12, 1998·Journal of Molecular Biology·P Chène
Apr 13, 2000·Proceedings of the National Academy of Sciences of the United States of America·G LiuG Lozano
Dec 1, 2000·Nature·B VogelsteinA J Levine
Jan 1, 2003·Seminars in Cancer Biology·Dan Michael, Moshe Oren
Jun 27, 2003·Proceedings of the National Academy of Sciences of the United States of America·Shunsuke KatoChikashi Ishioka
Jun 28, 2005·Proteins·Kevin WieheZhiping Weng
Sep 30, 2005·Journal of Medicinal Chemistry·Marcel L VerdonkRobin Taylor
Jan 18, 2006·Bioorganic & Medicinal Chemistry·Ramy FaridRobert A Pearlstein
Jan 20, 2006·Journal of Medicinal Chemistry·Woody ShermanRamy Farid
Apr 8, 2006·Cell Death and Differentiation·M F Lavin, N Gueven
Sep 5, 2006·Cellular and Molecular Life Sciences : CMLS·X-B QiuL Wang
Aug 21, 2009·Nature Reviews. Cancer·Ran Brosh, Varda Rotter
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Apr 7, 2010·The Journal of Biological Chemistry·Kazutoyo Terada, Yuichi Oike
Sep 20, 2011·Cancer Letters·Jason N SterrenbergAdrienne L Edkins
Jan 11, 2013·Nature Reviews. Cancer·Mark WadeGeoffrey M Wahl
Jun 12, 2013·Annual Review of Biochemistry·Yujin E KimF Ulrich Hartl
Sep 28, 2013·Nature Genetics·Giovanni CirielloChris Sander
Mar 22, 2014·Cancer Cell·Patricia A J Muller, Karen H Vousden
Dec 1, 2004·Drug Discovery Today. Technologies·Christopher A Lipinski
Apr 8, 2015·The Journal of Biological Chemistry·Rama K MishraMala Shanmugam
Jul 3, 2015·Current Computer-aided Drug Design·Rama K Mishra, Jasbir Singh
Oct 20, 2015·Journal of Chemical Information and Modeling·Teague Sterling, John J Irwin
Nov 20, 2015·Journal of Chemical Theory and Computation·Edward HarderRichard A Friesner
Feb 27, 2016·F1000Research·Wilson JengFrancis T F Tsai
Oct 28, 2016·Nature Cell Biology·Alejandro ParralesTomoo Iwakuma
Aug 9, 2017·Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research·Stephanie R VillaBrian T Layden
Sep 9, 2017·Cell·Edward R Kastenhuber, Scott W Lowe
Sep 10, 2017·EMBO Reports·Arindam DattaSusanta Roychoudhury
Sep 25, 2017·International Journal of Molecular Sciences·Sentiljana GumeniIoannis P Trougakos
Nov 4, 2017·Cell Death and Differentiation·Evan H BaughChang S Chan
Nov 4, 2017·Cell Death and Differentiation·Michael P Kim, Guillermina Lozano

❮ Previous
Next ❯

Software Mentioned

BLAST
GraphPad
OPLS3
PSI
Surflex
Schrödinger
Prism
MolProbity

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.