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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
106
71-POS
Board 31
Effects of Change-of-Function Mutations on Helix Stability in the Intrinsically Disordered
Τ1-Core Activation Domain of the Glucocorticoid Receptor
Lennart Nilsson
, Evdokiya Salamanova, Joana Paulo, Alok Juneja, Anthony Wright.
Karolinska Institutet, Huddinge, Sweden.
Intrinsically disordered proteins hold important functions in the cell, such as regulation of
transcription and translation, signalling, storage of small molecules and self-assembly of
macromolecular units in active complexes. The lack of a compact 3D-structure or folding only
upon binding to their targets is related to the specific rôle of the unstructured regions. The
glucocorticoid receptor belongs to a family of ligand-inducible nuclear receptors, and two of its
domains (tau1 and tau2) have shown conserved activity after they have been removed from the
receptor entity[1]. The disordered core region of the tau1-domain consists of 58 amino acids. It
carries most of the activity and has shown a helical propensity in hydrophobic solvents. We have
investigated structural effects of change-of-function mutations[2] in the tau1-core transactivation
domain in the glucocorticoid receptor. Based on our previous experience with the Aβ-peptide[3],
where we have also identified small peptide like molecules that stabilize the helix conformation
of Aβ, we have performed hundreds of 200+ ns molecular dynamics simulations to correlate the
experimental activities of the wild type and mutant peptides to their helical propensity and their
effect on activity.
1. Almlöf T, Ford J, Gustafsson J A, Wright A P (1997) Role of hydrophobic amino acid clusters
in the transactivation activity of the human glucocorticoid receptor. Mol Cell Biol. 17(2): 934–
945.
2. Almlöf, T., Wallberg, A. E., Gustafsson, J.-Å., and Wright, A. P. H. (1998) Role of Important
Hydrophobic Amino Acids in the Interaction between the Glucocorticoid Receptor τ1-Core
Activation Domain and Target Factors, Biochemistry 37, 9586-9594.
3. Ito, M., Johansson, J., Strömberg, R., and Nilsson, L. (2012) Effects of Ligands on Unfolding
of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics
Simulations, PLoS ONE 7, e30510.