[Todos] Seminarios DQIAyQF INQUIMAE- Viernes 15, 13h

[sara elizabeth bari]

Seminarios del Dpto. de Química Inorgánica, Analítica y Química Física / INQUIMAE

FCEyN - Universidad de Buenos Aires

http://www.qi.fcen.uba.ar/es

 

2do. Cuatrimestre, 2006

 

  

Viernes 15 de Septiembre, 13.00h
Aula Seminarios, DQIAyQF- INQUIMAE

Ciudad Universitaria, Pab. II, Piso 3

 

 

Munir S. Skaf
Insituto de Química. UNICAMP, Campinas, Brasil
 
 
Ligand Dissociation from Nuclear Receptors: Insights from Molecular Dynamics
 

 

Nuclear receptors (NR) comprise a family of key proteins responsible for regulating gene transcription. Transcriptional activation (deactivation) mechanisms are triggered by the binding (unbinding) of small hydrophobic molecules (hormones) to the ligand binding domain (LBD) of nuclear receptors. The NR superfamily includes receptors for thyroid hormone, retinoids, steroids, vitamin D, xenobiotics, fatty acids, bile acids and cholesterol derivatives, and orphan receptors for which ligands have not been identified. NRs play widespread roles in development, homeostasis and disease, and, consequently, are major targets for pharmaceutical development. Nuclear Receptor (NR) ligands occupy a pocket that lies within the core of the NR ligand binding domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein surface. Thus, significant NR conformational rearrangements must accompany ligand binding and release. The precise nature of these processes, however, remains poorly understood. In this talk, I will present results of Locally Enhanced Sampling (LES) Molecular Dynamics computer simulations which has been utilized to predict molecular motions of X-ray structures of thyroid hormone receptor (TR) LBDs and determine events that permit ligand escape. We find that the natural ligand (T3) dissociates from the TRa1 LBD along three competing pathways (Paths I-III) involving different LBD regions. We also propose that different escape paths are preferred in different situations, implying that it will be possible to design NR ligands that only associate stably with their cognate receptors in specific cellular contexts. The relative importance of putative pathways I-III is investigated using Steered Molecular Dynamics simulations. Our results show that the likeliest route for ligand dissociation from TR involves the highly mobile region at the bottom of the LBD (Path III), and that this mechanisms is favored by the replacement of hydrophilic interactions of the polar end of the ligand with the protein by ligand-water (external) interactions. Further analysis of the role played by surrounding water molecules suggests effective strategies for developing novel, high affinity, TR ligands. Some results concerning ligand selectivity towards different protein isoforms will also be presented.


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