AR BF3 BINDERS · Identification of the protein binders of the androgen receptor BF3 pocket, an allosteric modulator of AF2 coactivator recruitment
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2009-02-01 → 2013-01-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Андрогенният рецептор и специфичната му повърхност (BF3) се анализират, за да се разбере как протеините, свързани с нея, променят работата на рецептора. Това помага за разбирането на механизмите при рака на простатата и синдромите на андрогенна нечувствителност.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Identification of the protein binders of the androgen receptor BF3 pocket, an allosteric modulator of AF2 coactivator recruitment
Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. We previously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. We have combined experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicated that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganise into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We hypothesise that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design to find alternative therapeutics against prostate cancer.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITAT DE BARCELONA · BarcelonaКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз