University of Eastern Finland, Kuopio Campus
Supervisor: Mikael Peräkylä
Nuclear receptors (NRs) are transcription factors that can be activated by ligands. Binding of an agonist leads to conformational change in the ligand binding domain (LBD) of the NR and interaction with co-activator protein complex leading to transcription of a target gene. Without an agonist or with an antagonist a co-repressor protein complex is bound to LBD and the target gene is repressed.
Many NRs function as homo- or heterodimers. Often the partner protein in a heterodimer is RXR (Retinoid X receptor). NRs can be classified to permissive and non-permissive receptors on the basis of the dimer's response to ligands. Permissive receptors can be activated also with the partner protein's ligand and they give full response when ligands are bound to both receptors of the dimer, whereas non-permissive receptors do not react on the partner protein's ligand, but give a full response with their own ligand.
This Ph.D. project can be divided into three subprojects:
1a) Mechanism of permissivity at molecular level.
1b) Conformational/ dynamical factors important for NR activity.
2) Predicting formation and activity of heterodimer complexes of various NRs
3) Development of novel ligands to nuclear receptors: activities and affinities of ligand molecules.
These studies will be carried out with computational methods. For the molecular dynamic simulations, the software packages AMBER and GROMACS are used. The work will be done in close collaboration with the experimental groups of the University of Kuopio.