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Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface
Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearin...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2004
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC509409/ https://www.ncbi.nlm.nih.gov/pubmed/15328534 http://dx.doi.org/10.1371/journal.pbio.0020274 |
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author | Hur, Eugene Pfaff, Samuel J Payne, E. Sturgis Grøn, Hanne Buehrer, Benjamin M Fletterick, Robert J |
author_facet | Hur, Eugene Pfaff, Samuel J Payne, E. Sturgis Grøn, Hanne Buehrer, Benjamin M Fletterick, Robert J |
author_sort | Hur, Eugene |
collection | PubMed |
description | Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearing aromatic-rich motifs, while responding poorly to coactivators bearing the leucine-rich “NR box” motifs favored by other nuclear receptors. Under normal conditions, interactions with these AR-specific coactivators through aromatic-rich motifs underlie targeted gene transcription. However, during prostate cancer, abnormal association with such coactivators, as well as with coactivators containing canonical leucine-rich motifs, promotes disease progression. To understand the paradox of this unusual selectivity, we have derived a complete set of peptide motifs that interact with AR using phage display. Binding affinities were measured for a selected set of these peptides and their interactions with AR determined by X-ray crystallography. Structures of AR in complex with FxxLF, LxxLL, FxxLW, WxxLF, WxxVW, FxxFF, and FxxYF motifs reveal a changing surface of the AR coactivator binding interface that permits accommodation of both AR-specific aromatic-rich motifs and canonical leucine-rich motifs. Induced fit provides perfect mating of the motifs representing the known family of AR coactivators and suggests a framework for the design of AR coactivator antagonists. |
format | Text |
id | pubmed-509409 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2004 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-5094092004-08-24 Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface Hur, Eugene Pfaff, Samuel J Payne, E. Sturgis Grøn, Hanne Buehrer, Benjamin M Fletterick, Robert J PLoS Biol Research Article Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearing aromatic-rich motifs, while responding poorly to coactivators bearing the leucine-rich “NR box” motifs favored by other nuclear receptors. Under normal conditions, interactions with these AR-specific coactivators through aromatic-rich motifs underlie targeted gene transcription. However, during prostate cancer, abnormal association with such coactivators, as well as with coactivators containing canonical leucine-rich motifs, promotes disease progression. To understand the paradox of this unusual selectivity, we have derived a complete set of peptide motifs that interact with AR using phage display. Binding affinities were measured for a selected set of these peptides and their interactions with AR determined by X-ray crystallography. Structures of AR in complex with FxxLF, LxxLL, FxxLW, WxxLF, WxxVW, FxxFF, and FxxYF motifs reveal a changing surface of the AR coactivator binding interface that permits accommodation of both AR-specific aromatic-rich motifs and canonical leucine-rich motifs. Induced fit provides perfect mating of the motifs representing the known family of AR coactivators and suggests a framework for the design of AR coactivator antagonists. Public Library of Science 2004-09 2004-08-24 /pmc/articles/PMC509409/ /pubmed/15328534 http://dx.doi.org/10.1371/journal.pbio.0020274 Text en Copyright: © 2004 Hur et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hur, Eugene Pfaff, Samuel J Payne, E. Sturgis Grøn, Hanne Buehrer, Benjamin M Fletterick, Robert J Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface |
title | Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface |
title_full | Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface |
title_fullStr | Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface |
title_full_unstemmed | Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface |
title_short | Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface |
title_sort | recognition and accommodation at the androgen receptor coactivator binding interface |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC509409/ https://www.ncbi.nlm.nih.gov/pubmed/15328534 http://dx.doi.org/10.1371/journal.pbio.0020274 |
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