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Computational studies of nuclear receptors structural dynamics

Research unit

UMR 7104 - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
1 rue Laurent Fries 67404 ILLKIRCH

Group

Name: Modélisation Moléculaire/Biocomputing

Group leader: DEJAEGERE Annick - annick@igbmc.fr

Group leader's phone: 0368854721

Website: Visit website

Group organization:
- Chercheurs: 3
- ITA: 1
- Doctorants: 1
- Post-Docs: 3
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) A. Belorusova, J. Eberhardt, N. Potier, R.H. Stote, A. Dejaegere, N. Rochel
Structural insights into the molecular mechanism of Vitamin D Receptor activation by lithocholic acid involving a new mode of ligand recognition
J. Med. Chem. 2014, 57, 4710-4719

2) Y. Chebaro, I. Amal, N. Rochel, C. Rochette-Egly, R. H. Stote, A. Dejaegere
Phosphorylation of the Retinoic Acid Receptor alpha induces a mechanical allosteric regulation and changes in internal dynamics.
Plos Comp Biol. 2013, 9 (4), e1003012

3) T. Gaillard, B. B. L. Schwarz, Y. Chebaro, R.H. Stote and A. Dejaegere
Protein structural statistics with PSS
J. Chem. Inf. Model. 2013, 53, 2471-2482

About PhD

PhD Director: DEJAEGERE Annick - annick@igbmc.fr

Phone: 0368854721

Junior advisor: oui

Co-tutely: non

Co-Director: STOTE Roland
University of Co-Director: Unistra

About PhD topic :

Title: Computational studies of nuclear receptors structural dynamics

Project: Nuclear receptors (NR) are the largest family of transcription factors that regulate the transcription of genes in metazoans. They control many processes in the cell cycle, including differentiation, apoptosis, development, reproduction and homeostasis. An important common feature of NRs is that their regulation of gene expression is ligand dependent. This ligand dependent activity makes NRs central targets for the development of therapeutic compounds for many diseases such as diabetes, arteriosclerosis, inflammatory diseases, cancer, etc. NRs can be considered molecular signaling nanomachines, which integrate different signals (ligand recognition, post-translational modifications) and trigger the appropriate transcriptional responses. Our research team uses numerical simulations to decipher the molecular level mechanisms that underlie this signaling activity. In addition to an interest in a fundamental understanding cell signaling mediated by nuclear receptors, this work contributes knowledge important for the the development of new active compounds, particularly in view of the development of selective modulators.
This PhD project will focus on the study of the glucocorticoid receptor (GR), an important mediator of inflammatory reactions. GR is a steroid receptor, as are the androgen (AR), progesterone (PR), estrogen (ER) receptors. The most widely accepted mechanism is one where GR is active as a homodimer. NRs have a common architecture consisting of an N-terminal variable region, a conserved DNA binding domain (DBD), a variable hinge region, a conserved ligand binding domain (LBD ) and a variable C-terminal region. Structures of GR DBD dimers, as well as dimeric structures of the respective LBDs, have been determined. The architecture of the GR DBD dimers is similar to DBD structures determined for other members of this subfamily of nuclear receptors, but surprisingly, in crystallographic structures the GR LBD homodimerizes with a different interface with respect to other NRs.(1)
The aim of this PhD project is to characterize the structural dynamics of the GR ligand binding domain and to characterize the different interaction surfaces that the LBD can form with different partners. The identification of the interaction interfaces of GR LBD is an important issue not only for understanding gene regulation by GR, but also in view of recent data that indicate cross regulation between different nuclear receptors.
This project will in particular focus on the recently characterized cross-regulation between GRalpha and PPARalpha receptors (2). This cross-regulation involves interaction between the two receptors, but it is poorly understood from a molecular perspective. Experimentally, coimmunoprecipitation experiments showed that the presence of the GRalpha LBD was essential for observing an interaction with PPARalpha (2). The project will involve close exchange between theory and experiment and will be developed in collaboration with K. De Bosscher (Ghent University, Belgium) and Isabelle Billas (IGBMC), who are involved in experimental studies of GRalpha.
1.       R.K. Bledsoe et al. Cell 110, 93-105 (2002).
2.       N. Bourgane et al. . Proc. Natl. Acad. Sci. USA 106, 7397, (2009)

Wished skills: This project is aimed at biologists/bioinformaticians, computer scientists, chemists or physicists with a strong motivation for developing innovative methods in molecular modeling and apply them to biologically relevant problems. A working knowledge of the UNIX/Linux operating system, and programming skills are necessary, as well as knowledge in structural biology (protein structure and principle of macromolecular recognition).

Expertises which will be acquired during the training: The thesis student will develop his scientific culture at the biology-chemistry-physics interface and will reinforce his/her practical training in computers and programming, as well as in cutting-edge methods for numerical simulation and molecular modeling. This background will open opportunities for industrial (mainly pharmaceutical or software companies) as well as academic careers.