Fecha y hora: Viernes, 16 de febrero de 2024. 12:00 h.
La Dra. Eva Estébanez-Perpiñá impartirá en Navarrabiomed el viernes, 16 de febrero, el seminario: "Prostate cancer: Understanding Nuclear Receptor Form and Function using Structural Biology". La ponente es profesora del Departamento de Bioquímica y Biomedicina Molecular de la Facultad de Biología dentro del Instituto de Biomedicina de la Universidad de Barcelona (IBUB).
Entrada libre hasta completar aforo para profesionales de cualquier centro adscrito a IdiSNA (no es necesaria inscripción previa). Idioma de la sesión: castellano.
- Abstract Talk:
Oligomerization of androgen (AR) and glucocorticoid (GR) receptors remains disputed. We identified four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant GR homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR and illustrates the unique flexibility of GR’s LBD and suggests different dimeric conformations within cells.
In the case of AR, The contribution of LBD dimerization to the physiological activity of the receptor has remained controversial for a long time. We presented the crystal structure of an AR-LBD homodimer for the first time, along with biochemical and functional evidence of its relevance in vivo. The dimerization of the AR is crucial for its activity, for the pharmacological outcome to major antiandrogen blockbusters for prostate cancer patients and to understand rare sex development disorders in children and a rare neurodegeneration in adults.
We have recently also thoroughly studied the effects of selected mutations that span the complete dimer interface of AR-LBD using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine.
- Biosketch:
Prof. Estébanez-Perpiñá obtained simultaneously her degrees of Biochemistry and Psychology-Neurosciences from the Autonomous University of Barcelona (UAB). She did her Ph.D. in Structural Biology under the direction or Prof. Dr. Robert Huber, 1988-Nobel Prize Laureate in Chemistry at the Max-Planck-Institute für Biochemie in Martinsried (Munich, Germany), where she solved the first crystal structures of three human proteases named Granzymes, key caspase activators involved in auto-immune disorders. For her postdoctoral studies she went to the University of California, San Francisco, to work under the mentorship of Prof. Robert J. Fletterick and Prof. John. D. Baxter, where she focused on the structure-function relationship of several human nuclear receptors and the AMPA Receptor. Eva discovered the first allosteric pocket in the Androgen Receptor (AR) and coined the term BF-3 pocket, as well as the first allosteric modulators of several nuclear receptors.
She started her independent laboratory at the Institute of Biomedicine of the University of Barcelona (IBUB-UB), where she is Tenured Aggregate Professor and currently is up for promotion as Full Professor. Her laboratory studies oligomerization of human Glucocorticoid Receptor (GR) and AR and uses X-ray crystallography and complementary bio-chemical/physical and cellular methods. Her team recently elucidated the first structure of the dimeric form of AR ligand binding domain, a structure long sought for as well as the most complete catalogue of GR oligomers.
Eva also teaches 250 hours yearly at the Degree of Biochemistry and Master of Biotechnology UB. She collaborates with numerous international and national academic groups and pharmaceutical companies to design improved therapeutics to fight prostate cancer and auto-immune diseases. Her publications can be found at Nature (2023), Nature Communications (2017), Nature Structural and Molecular Biology (2003), Science Advances (2023), Nucleic Acids Research (2022), Proceedings of the National Academy of Sciences (2022; 2017) and many more. Her current laboratory includes 1 postdoctoral fellow, 2 Ph.D. students, 1 technician, and 2 undergrad TFG students.