Evaluation of ligand-dependent changes in AR structure using peptide probes

Molecular Endocrinology
Ching-Yi Chang, D P McDonnell

Abstract

Mutations in the AR are frequently found in relapsed prostate cancers, some of which permit antiandrogens as well as nonandrogenic compounds to function as androgens. However, the molecular mechanism(s) by which these mutations enable this aberrant AR pharmacology is still unknown. To explore this issue, we used a series of LxxLL-containing peptides (L, leucine; x, any amino acid) to probe the conformation of the AF-2/coactivator binding pocket of AR and AR mutants when complexed with different ligands. We have identified in a previous study two peptides that bind to the wild-type AR in an agonist-dependent manner. Interestingly, we found these same peptides also interacted with several AR variants that are frequently found in antihormone refractory prostate cancers, in the presence of either androgens or antiandrogens. This suggests that the agonist activity of antiandrogens and other physiologically relevant ligands occurs because they, in the background of these mutations, allow AR-AF2 to adopt an active conformation. Initially, this result appeared to contradict the findings of others that suggest that coactivator binding to AR-AF2 is not required for AR activity. In probing this paradox further, however, we determined that...Continue Reading

Citations

Sep 15, 2005·Chemical Reviews·Wenqing GaoJames T Dalton
Aug 26, 2006·Nature Clinical Practice. Endocrinology & Metabolism·Shalender BhasinJames T Dalton
Nov 23, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jeffrey N MinerAndres Negro-Vilar
Feb 28, 2007·Molecular and Cellular Biology·Chun-Song YangBryce M Paschal
Oct 15, 2008·Molecular Cancer Therapeutics·Myles C HodgsonSteven P Balk
Sep 3, 2011·Journal of Carcinogenesis·Peter E Lonergan, Donald J Tindall
May 25, 2011·Molecular and Cellular Endocrinology·Mikhail N ZakharovRavi Jasuja
Jan 25, 2013·Medicinal Research Reviews·Laura Caboni, David G Lloyd
Mar 19, 2016·Andrology·G C ShuklaS Gupta
Jul 28, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Cara L BenjaminJorge A Piedrahita
Apr 30, 2005·Trends in Pharmacological Sciences·Ching-yi Chang, Donald P McDonnell
Jul 22, 2015·The Journal of Steroid Biochemistry and Molecular Biology·Eric Biron, François Bédard
Aug 30, 2011·Molecular and Cellular Endocrinology·Dennis J van de WijngaartGuido Jenster
Sep 25, 2004·The Prostate·Hiroshi MiyamotoChawnshang Chang
Dec 17, 2008·Nuclear Receptor Signaling·Ramesh NarayananJames T Dalton
Apr 15, 2004·Endocrine Reviews·Cynthia A Heinlein, Chawnshang Chang
Jun 5, 2004·Molecular Endocrinology·Hendrikus J DubbinkJan Trapman
Sep 13, 2003·The Journal of Clinical Endocrinology and Metabolism·Dong Kun Lee, Chawnshang Chang
Feb 11, 2004·Endocrine Reviews·Carolyn L Smith, Bert W O'Malley
Jul 30, 2005·Molecular Endocrinology·Ching-Yi ChangDonald P McDonnell
Aug 30, 2005·Endocrine Reviews·David J MulhollandColleen C Nelson
Apr 12, 2019·International Journal of Environmental Research and Public Health·Lucia LanciottiSusanna Esposito
May 13, 2006·The Journal of Biological Chemistry·Dennis J van de WijngaartHendrikus J Dubbink
Sep 6, 2005·Journal of Cell Science·Pascal FarlaAdriaan B Houtsmuller

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