Research Overview

The androgen receptor (AR) belongs to the nuclear receptor family, and is a key regulator of prostate cancer growth. AR is therefore a crucial target for prostate cancer therapies. We have obtained structural information of the AR hormone binding domain (LBD) in complex with peptides derived from the AR physiological coactivators ARA70 and P160 family of coactivators (i.e. GRIP1 and RAC3). These structural models of the protein-peptide complexes determined by X-ray crystallography clarify the long standing question of why the same surface on the AR LBD is unique amongst the nuclear receptors in its capability to bind to different classes of domains, characterized by hydrophobic sequence motifs, presented by its coactivator partners. We hope to inhibit AR activation by blocking this surface, preventing AR LBD-coregulatory proteins interaction, proposing a structure-based drug design strategy that combines our structural information, combinatorial chemistry, and bioinformatics.

Research Interests

Our primary goal will be the development of a new therapeutic approach to treat prostate cancer using the molecular insights gained from different multidisciplinary approaches.

Study the role of androgen receptor´s newly described regulatory surfaces in its transcriptional activity.

Identification of the biological partners of the surface pocket named Binding Function 3 (BF3).

Biographical Sketch

Eva Estébanez-Perpiñá studied at the Universitat Autonoma de Barcelona (UAB), where she obtained her degrees in Biochemistry and Psychology (Psychobiology). After that she did her PhD (Tesis) with the Nobel Laureate Prof. Robert Huber and Prof. Wolfram Bode at the Max Planck Institut fuer Biochemie in Martinsried (Munich, Germany), where she gradutated in 2002. After a short postdoctoral period there she joined the lab of Prof. Robert J. Fletterick at the University California, San Francisco (UCSF) to study the structure-function relationships of nuclear receptors such as the androgen receptor and the thyroid receptor. She is at the IBUB since January 2008.

Recent Publications

Estébanez-Perpiñá E, Arnold LA, Jouravel N, Togashi M, Blethrow J, Mar E, Nguyen P, Phillips KJ, Baxter JD, Webb P, Guy RK, Fletterick RJ. A surface on the androgen receptor that allosterically regulates coactivator binding. Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16074-9. Epub 2007 Oct 2.

Estébanez-Perpiñá E, and Fletterick RJ. The Androgen Receptor Coactivator Binding Interface. Book chapter, in press Springer-Verlag 2008.

Estébanez-Perpiñá E, Jouravel N, and Fletterick RJ. Perspectives on designs of antiandrogens for prostate cancer. Expert Opinion on Drug Discovery. 2007 Oct, Vol. 2, No. 10, Pages 1341-1355

Estébanez-Perpiñá E, Arnold LA, Jouravel N, Togashi M, Blethrow J, Mar E, Nguyen P, Phillips KJ, Baxter JD, Webb P, Guy RK, Fletterick RJ. Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor. Mol Endocrinol. 2007 Dec;21(12):2919-28. Epub 2007 Sep 6.

Arnold LA, Kosinski A, Estébanez-Perpiñá E, Fletterick RJ, Guy RK. Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships. J Med Chem. 2007 Nov 1;50(22):5269-80. Epub 2007 Oct 5.

Arnold LA, Estébanez-Perpiñá E, Togashi M, Shelat A, Ocasio CA, McReynolds AC, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK. A high-throughput screening method to identify small molecule inhibitors of thyroid hormone receptor coactivator binding. Sci STKE. 2006 Jun 27;2006(341):pl3.

Arnold LA, Estébanez-Perpiñá E, Togashi M, Jouravel N, Shelat A, McReynolds AC, Mar E, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK. Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators. J Biol Chem. 2005 Dec 30;280(52):43048-55. Epub 2005 Oct 31.

Estébanez-Perpiñá E, Moore JM, Mar E, Delgado-Rodrigues E, Nguyen P, Baxter JD, Buehrer BM, Webb P, Fletterick RJ, Guy RK. The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor. J Biol Chem. 2005 Mar 4;280(9):8060-8. Epub 2004 Nov 24.

Group Members

Open positions!

If you are interested in joining the lab at the beginning of 2009 as postdoc, PhD student or research assistant please send us your CV and cover letter: evaestebanez@ub.edu

Si estás interesada/o en unirte al laboratorio a principios de 2009 como postdoc, PhD o asistente de investigación, envíanos un email con tu CV y una carta de presentación a: evaestebanez@ub.edu