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Molecular dynamics of androgen nuclear receptors: native structure and functionally important mutants

Grant number: 08/01236-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2008
Effective date (End): August 31, 2009
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Munir Salomao Skaf
Grantee:Karen Cacilda Weber
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:06/00182-8 - Structural biophysics of nuclear receptors and related proteins, AP.TEM

Abstract

Androgen receptor (AR) is a member of the nuclear receptor superfamily, which is composed of over 100 members that are major targets for drug discovery. AR has key roles in development, maintenance, and regulation of male reproductive system. AR mutations are correlated to a series of disorders such as androgen insensitivity syndrome (AIS), prostate cancer, and spinal and bulbar muscular atrophy. The majority of AR mutations occurs by single amino acid exchange and can result in increased gene transactivation as well as loss of AR function. Like most nuclear receptors, AR cellular activity is mainly mediated through hormone binding. Nevertheless, the ligand-induced conformational changes of the AR ligand binding domain are not well determined. Molecular dynamics simulations are essential to overcome this limitation and to provide new information on the mechanisms of activation and inhibition in a molecular level. The main focus of our project is the determination of structural and dynamic changes occurring upon ligand binding in the mutant forms of AR, compared to the wild-type. We expect to generate relevant knowledge about the molecular level behavior of several AR mutants in association to their functional implications and to contribute to the understanding of the molecular basis of syndromes associated to AR mutations, which can be useful for AR ligand design. This proposition is part of an ongoing collaboration between the groups of Profs. Munir Skaf (Unicamp) and Igor Polikarpov (IFSC), funded by Projeto Temático FAPESP (2006/00182-8). (AU)