AR BF3 BINDERS

"Identification of the protein binders of the androgen receptor BF3 pocket, an allosteric modulator of AF2 coactivator recruitment"

Coordinatore	UNIVERSITAT DE BARCELONA    more  Organization address address: GRAN VIA DE LES CORTS CATALANES 585 city: BARCELONA postcode: 8007 contact info Titolo: Ms. Nome: Marina Cognome: Mateu-Guardia Email: send email Telefono: 34934035383 Fax: 34934035383
Nazionalità Coordinatore	Spain [ES]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2007-4-3-IRG
Funding Scheme	MC-IRG
Anno di inizio	2009
Periodo (anno-mese-giorno)	2009-02-01   -   2013-01-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITAT DE BARCELONA  Organization address address: GRAN VIA DE LES CORTS CATALANES 585 city: BARCELONA postcode: 8007 contact info Titolo: Ms. Nome: Marina Cognome: Mateu-Guardia Email: send email Telefono: 34934035383 Fax: 34934035383	ES (BARCELONA)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'The androgen receptor (AR) is a nuclear receptor (NR) that plays a central role in prostate cancer. The transcriptional activity of AR can be modulated though a newly described regulatory surface on its ligand binding domain (LBD). We call this surface BF3 (binding function 3), and I discovered it during my postdoctoral research. So far the only coregulatory proteins described are able to regulate AR activity by binding to the coactivator binding pocket (AF2), which is also located on the LBD surface. Both pockets, AF2 and BF3, are physically connected. In my numerous molecular structures of the AR LBD solved by Xray crystallography, I have been able to see that BF3 is an allosteric modulator of AF2. BF3 is able to influence whether coactivator proteins are correctly recruited to AF2 to start the transcriptional cascade of AR-dependent genes. Thanks to my discovery of several BF3-interacting chemical compounds we have been able to determine which conformational changes are propagated from BF3 to AF2 impairing AR activity. Such small molecules are an important starting point for structure-based drug design to identify novel AR regulators that may be used as new treatments for prostate cancer. I have also investigated what effect mutations in BF3 have on AR transcriptional activity. The topology, localization, and physico-chemical properties of BF3 indicate that it is a bona fide pocket for protein-protein interactions and it may have a physiological regulatory action on AR function in vitro and in vivo. The identification, characterization and crystallization of BF3-interacting proteins and their crystal structure determination alone or in complex with AR are the main objective of my future research. Such proteins may be a novel class of AR coactivators in particular, or coregulators of other steroid NR. These studies are relevant to the NR and for the pharmaceutical fields, as BF3-binders may be novel targets to alter AR function in prostate cancer.'