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The mechanism of allostery and binding of novel ligands on nuclear receptors

Nuclear receptors (NRs) are transcription factors, which regulate gene expression in response to ligand binding, a feature which makes them ideal drug targets. While many NRs like steroid hormone receptors function as homodimers, one group of NRs can form heterodimers with another NR called retinoid X receptor (RXR). Both partners of a heterodimer complex can bind a ligand, and different heterodimers respond to ligand binding differently. Some of these heterodimers can also be activated in an allosteric manner through ligand binding on RXR. 

The dissertation of MSc Tuomas Oravilahti utilizes molecular dynamics simulations to study the molecular level mechanism of allosteric activation of the peroxisome proliferator-activated receptor (PPARα)-RXRα heterodimer. It was found that allosteric activation may result from stabilization of the co‑activator binding site upon ligand binding to the heterodimeric partner.

In addition, structural determinants of several new estrogen receptor (ER) binders were explored in docking studies. Single amino acid differences in the ligand binding pockets of ERα and ERβ were found to contribute to the binding orientation of the compounds and selectivity between these two ER subtypes.

A rational design approach was used to discover novel structures for androgen receptor (AR) binders, by combining the existing features of ER binders, AR binders and a novel structural feature. In experimental tests, these compounds were found to bind to AR with high affinity and to inhibit AR activation comparably or better than the existing AR antagonists used in clinical practice.

The doctoral dissertation of Tuomas Oravilahti, entitled Computational studies on nuclear receptors: mechanism of allosterism and design of novel ligands, will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Björn Windshügel from Fraunhofer ITMP, and the Custos will be Adjunct Professor Tuomo Laitinen from the University of Eastern Finland. The public examination will be held in English online on 17 June 2021 starting at 12 noon.

Public examination online

Dissertation online