Logo Universitat de Barcelona The Institute of Biomedicine of the University of Barcelona (IBUB) imatge de maquetació
IBUB UB imatge de maquetació
imatge de maquetació
imatge de maquetació imatge de maquetació imatge de maquetació imatge de maquetació imatge de maquetació
imatge de maquetació
Eva Estébanez-Perpiñá, PhD
  Structural Biology of Human Nuclear Receptors

Current Research
Lab members
Publications
Funding
Lab Pictures
Contact
News
Current Research
Our laboratory studies several members of the family of nuclear receptors (NRs) that regulate gene expression in many tissues. There are 48 nuclear receptors in humans, some of them have their ligand and functions well-characterized, while others are regarded as orphans as their ligand or function is still not completely described. Among the steroid subclass of NRs, we study the androgen receptor (AR), which is implicated in prostate cancer, androgen insensitivity syndromes and the neurodegenerative Kennedy´s disease. AR is therefore a crucial therapeutical target. We propose a structure-based drug design strategy that combines our structural information obtained by X-ray crystallography, combinatorial chemistry, and bioinformatics to identify alternative ways to treat prostate cancer by targeting alternative sites on the AR surface.
The laboratory is also interested in the characterization of several orphan receptors with therapeutical potential as drug targets. We aim to visualize several NRs and their key protein and ligand interactions to understand their function in the cell under physiological or pathological conditions. We tackle the biological processes we study from a multidisciplinary approach using several biochemical and biophysical techniques.

Projects

Nuclear Receptors Structure and Function
Crucial to our work is the usage of protein crystallography/X-ray diffraction and other biophysical approaches to visualize the atomic details of NR structure and their key ligand and protein interactions

-Androgen Receptor Structure-Function and Drug Discovery
-
Study the role of androgen receptor´s regulatory surfaces AF-2 (Coactivator Binding) and BF-3 (Binding Function 3) pockets in its transcriptional activity.
- Allosteric modulators of AR function as therapeutic drugs to treat prostate cancer using the molecular insights gained from X-ray crystallography and SPR.
- Computational studies on androgen receptor regulatory surfaces. Unravel the relationship between AR regulatory surfaces, their conformational dynamics and biological functions.
- Identification and validation of biological protein partners of the BF-3 pocket.
- Elucidation of the molecular determinants underlying the neuromuscular neurodegenerative disorder (Kennedy´s disease) using a multidisciplinary approach.

Uncharacterized Orphan-receptors Structure-Function and Drug Discovery
-Unravel the crystal structure of uncharacterized orphan receptors and determine their key protein interactions.
-Drug-discovery approach to exploit their clinical applications.

 


Lab members

Eva Estébanez-Perpiñá, Ph.D. Group Leader
Eva studied at the Universitat Autònoma de Barcelona (UAB), where she obtained her degrees in Biochemistry and Psychology (Psychobiology). She did her Ph.D Thesis under the supervision of the Nobel Laureate Prof. Robert Huber and Prof. Wolfram Bode at the Max-Planck-Institut fuer Biochemie in Martinsried (Germany), where she graduated in 2002. After a short postdoctoral period there she joined in 2003 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 Institute of Biomedicine, University of Barcelona (IBUB) since January 2008.

Montse Montserrat Abella (Research Associate)
Montserrat is a highly experienced researcher with more than 25 years in the Pharmaceutical field. She is at the IBUB since February 2016.
Alba Alba Jiménez (PI-PII-TFG Student)
Alba is a Biomedicine student.
She is at the IBUB since January 2017.


   

Publications

2017
-Nadal M, Prekovic S, Gallastegui N, Helsen C, Abella M, Zielinska K, Gay M, Vilaseca M, Taulès M, Houtsmuller AB, van Royen ME, Claessens F, Fuentes-Prior P, Estébanez-Perpiñá E.
Structure of the homodimeric androgen receptor ligand-binding domain.
Nat Commun. 2017 Feb 6;8:14388. doi: 10.1038/ncomms14388.

- A Fenner
AR homodimerization is essential to function
Nature Reviews Urology. Researcher Highlight 2017 Feb 21. doi:10.1038/nrurol.2017.24 Published online

2016
-De Mol E, Fenwick RB, Phang CT, Buzón V, Szulc E, de la Fuente A, Escobedo A, García J, Bertoncini CW, Estébanez-Perpiñá E, McEwan IJ, Riera A, Salvatella X.
EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.
ACS Chem Biol. 2016 Sep 16;11(9):2499-505. doi: 10.1021/acschembio.6b00182.

2015
-Gallastegui N, MacKinnon JAG, Fletterick RJ. and Estébanez-Perpiñá E. Advances in our structural understanding of orphan nuclear receptors.
Trends Biochem Sci. 2015 Jan;40(1):25-35. doi: 10.1016/j.tibs.2014.11.002. Review

2014
-Gallastegui N, MacKinnon JAG, Fletterick RJ. and Estébanez-Perpiñá E. Advances in our structural understanding of orphan nuclear receptors.
Trends Biochem Sci. (TiBS) 2014 Dec 10. pii: S0968-0004(14)00206-0. doi: 10.1016/j.tibs.2014.11.002.

-MacKinnon JAG, Gallastegui N, Osguthorpe DJ, Hagler AT and Estébanez-Perpiñá E.
Allosteric mechanisms of nuclear receptors: Insights from computational simulations.
Mol Cell Endocrinol. 2014 Jun 6. pii: S0303-7207(14)00166-X. doi: 10.1016/j.mce.2014.05.017.

-Jehle K, Cato L, Neeb A, Muhle-Goll C, Jung N, Smith EW, Buzon V, Carbo LR, Estébanez-Perpiña E, Schmitz K, Fruk L, Luy B, Chen Y, Cox MB, Brase S, Brown M, Cato AC.
Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif.
J Biol Chem. 2014 Feb 13.

-Gallastegui N. and Estébanez-Perpiña E.
Thinking Outside the Box: Alternative Binding Sites in the Ligand Binding Domain of Nuclear Receptors.
Invited Book Chapter, Springer Verlag. Book: Nuclear Receptors - From Structure to the Clinic.

2013
-N. Gallastegui and E. Estébanez-Perpiña. Invited Book Chapter, Nova Publishers. Chapter 3.
Structural and Functional Analysis of the Androgen Receptor in Disease. Book: Androgen Receptor: Structural Biology, Genetics and Molecular Defects.
ISBN: 978-1-62948-693-2.

2012
-Estruch SB, Buzón V, Carbó LR, Schorova L, Lüders J, Estébanez-Perpiñá E.
The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function.
PLoS One. 2012;7(6):e37963. Epub 2012 Jun 4.

-Grosdidier S, Carbó LR, Buzón V, Brooke G, Nguyen P, Baxter JD, Bevan C, Webb P, Fernández-Recio J., Estébanez-Perpiñá E.
Allosteric conversation in the androgen receptor ligand-binding domain surfaces.
Mol Endocrinol. 2012 Jul;26(7):1078-90. Epub 2012 May 31.

2011
-Buzón V, Carbó LR, Estruch, SB, Fletterick RJ. and Estébanez-Perpiñá E.
A surface on the androgen receptor that allosterically regulates coactivator binding. Invited review, Special issue on Nuclear Receptor Dynamics.
Molecular and Cellular Endocrinology (MCE), in press.

2009
-Estébanez-Perpiñá E, and Fletterick RJ.
The Androgen Receptor Coactivator Binding Interface. Invited book chapter by Springer-Verlag.
ISBN 9780387691794.

2008
-Cruz, L.A, Estébanez-Perpiñá E, Pfaff S., Borngraeber, S., Bao, N., Blethrow, J., Fletterick RJ, and England. P.
6-Azido-7-nitro-1,4,-dihydroquinoxaline-2,3-dione (ANQX) forms and irreversible bond to the active site of the GluR2 AMPA receptor.
J Med Chem. 2008 Sep 25;51(18):5856-60.

-Sala, F., Estébanez-Perpiñá E, Balada, F, Garau A., Martí-Carbonell, MA.
Behav Brain Res, 2008 Apr 9; 188(2):348-54

2007
-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.

-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.

-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.

2006
-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.

2005
-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.

-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.



Funding

2017 - Bayer, Berlin-Grants-4-Targets

2015 - Medivation Inc., San Francisco CA, USA

SGR Grup Reconegut per la Generalitat de Catalunya

MINECO BFU2014-60135-P - Postdoctorate fellowship

Kind Donations from Individuals (Donacions Particulars)

2012 - Bayer Schering Pharma (BSP) Berlin-Grants-4-Targets

Orphagen Pharmaceuticals and Therapeutics, San Diego CA, USA

Sponsorship by Shifa Pharmaceuticals, Malvern PA, USA

European Union (EU)-Marie Curie Actions International Reintegration Grant (IRG) (Code 224812:AR BF3 Binders)

MICINN (Code:SAF2008-03562: Identificación de las Proteïnas de Unión a BF3)

MICINN (Code:SAF2011-29681: Caracterización Estructural de complejos entre AR y Coreguladores)

MICINN Programa 2007-Ramón y Cajal

Fundació La Marató TV3 (Code: Identificación de los Agregados de AR que causan la Atrofia Muscular Espinal Bulbar)

Bayer Schering Pharma (BSP) Berlin (Code FBG7443: Fundació Bosch i Gimpera-UB)

Bayer Schering Pharma (BSP) Berlin (Code FBG28344: Fundació Bosch i Gimpera-UB)

Sponsorship by Medivation Inc. IBUB-Nuclear Receptors:Meet the Family Symposium, Barcelona 21st September, 2011


Lab Pictures

Foto grup Eva



Contact

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

Institut de Biomedicina (IBUB), Universitat de Barcelona (UB)
Parc Cientific de Barcelona (PCB)
Ph office: (00-34) 93-403-11-19
Cell Ph: (00-34) 696-73-4226
Edifici Helix (Lab ES03A08, Office B08)
Baldiri Reixac, 15-21, 08028 Barcelona

 

imatge de maquetacióNews

2017
Researchers find a new human androgen receptor structure, key target for the treatment of prostate cancer
http://www.ub.edu/web/ub/en/menu_eines/noticies/2017/02/008.html
http://www.fbg.ub.edu/post/en/546

Identificada una diana clave para tratar el cáncer de próstata
Investigadores catalanes han descrito por primera vez la estructura tridimensional dimérica del dominio de unión a las hormonas androgénicas del receptor humano de andrógenos. Esta nueva estructura permite explicar más de 40 mutaciones identificadas en pacientes de cáncer de próstata, uno de los más comunes en el mundo.
http://www.agenciasinc.es/Noticias/Identificada-una-diana-clave-para-tratar-el-cancer-de-prostata

AR homodimerization is essential to function
Nature Reviews Urology (2017) doi:10.1038/nrurol.2017.24

A new key target for the treatment of prostate cancer
An international research lead by Institute of Biomedicine of the University of Barcelona (IBUB) and the Research Institute of the Hospital de la Santa Creu i Sant Pau (IIB Sant Pau) shows, for the first time, the three-dimensional structure of the homodimeric androgen receptor ligand-binding domain. In order to solve the 3D structure of the protein, X-ray diffraction analyses have been conducted at the XALOC beamline of the ALBA Synchrotron.
https://www.albasynchrotron.es

2011
Francesc Villarroya and Eva Estébanez organize the IBUB-Symposia: Nuclear Receptors: Meet the Family
September 21st, Aula Magna, Faculty of Biology, UB, Avda Diagonal 645, Barcelona
Program and Invited Speakers

Four groups of the IBUB (M. Cascante, M. Pastor, C. Ciudad and E. Estébanez) in the Oncocat network.
The Oncocat network has been created to promote synergies in research in cancer in Catalonia.
http://www.biocat.cat/es/conoce-biocat

2010
Eva Estébanez together with Xavier Salvatella (IRB, Barcelona) and Leila Luheshi (Cambridge Univ) have been awarded a collaborative project by the Marató de TV3 with 397,000 Euro to study Kennedy´s disease, a rare neurodegenerative disease
http://www.tv3.cat/marato/es/projectes_financats_2009.htm

2009
The Nobel Laureate in Chemistry Robert Huber gives a conference titled Proteases and Their Regulation, from Molecular Structures to Application invited by Francesc Villarroya and Eva Estébanez.
Aula Magna, Faculty of Biology. Many ex-alumni of Robert Huber were also present in the audience


 

imatge de maquetació

imatge de maquetacióSeminars

2009
2010 2010 2011 2011 2012    
  2012 2012 2014 2015    
 
imatge de maquetació
imatge de maquetació © Universitat de Barcelona Edició: IBUB
Última actualització o validació: 06.03.2017
imatge de maquetació