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Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands

Paulo Cesar Telles de Souza
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas. Instituto de Química
Defense date:
Examining board members:
Pedro Geraldo Pascutti; Richard Charles Garratt; Carlos Henrique Inácio Ramos; Francisco Benedito Teixeira Pessine
Advisor: Munir Salomão Skaf

Nuclear receptors (NRs) are proteins that regulate the gene transcription and thus are important targets for drug development. NRs are composed of four structural domains. The most important of them is the Ligand Binding Domain (LBD), responsible for the selective recognition of ligands and activation of NR function. In this Doctoral Thesis, Molecular Dynamics (MD) Simulation are used to study two important NRs LBD: Thyroid Hormone Receptor (TR) and Estrogen Receptor (ER). Studies involving TR began by investigating a new second binding site of thyroid hormones (T3 and T4) in the TR LBD. It has been shown that hormones remain anchored to the second site and have high mobility and multiple binding modes. Estimates of dissociation DG indicate that this new site can exist in aqueous solution. T4 has the higher affinity and may be the natural ligand of this site. The second objetive of the Thesis was the molecular modeling of the TR LBD structure without ligands (apo-TR) by combining results of MD simulations and hydrogen deuterium exchange experiments. The obtained model of apo-TR shows that H12 a-helix is anchored in H3 which explains the hydration changes in this region indicated by the experiments. The third goal was to elucidate the molecular mechanisms that lead to changes in the activity of two TR mutations: M369Ra and P452Lb. Simulations of M369Ra indicate that the mutated residue can interact directly with T3 in the second binding site, explaining the increase of its affinity. Simulations of P452Lbsuggested that this mutation changes the H12 position, leading to loss of ligand interaction with the rst binding site and reduction of coactivator cavity. The last study investigated a new alternative conformation of ERb LBD, which has the potential to explain how this subtype promotes the partial repression of ERagene transcription. Calculation of DG between classic and alternative conformations indicate that the alternative is stable and the global minimum of free energy. (AU)

FAPESP's process: 09/14108-2 - Molecular dynamics simulations of nuclear receptors: ligand-protein free energy estimates
Grantee:Paulo Cesar Telles de Souza
Support type: Scholarships in Brazil - Doctorate