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Glucocorticoid Receptor Point Mutation V571M Facilitates Coactivator and Ligand Binding by Structural Rearrangement and Stabilization

Department of Structural Biology (P.C., K.F.K.), Karo Bio AB, Novum, and Department of Biosciences at Novum (P.C., L.N.), Karolinska Institutet, S-141 57 Huddinge, Sweden

Address all correspondence and requests for reprints to: Peter Carlsson, Karo Bio AB, Novum, S-141 57 Huddinge, Sweden. E-mail: peter.carlsson{at}karobio.se.

Two-point mutations in the human glucocorticoid receptor have been studied by computer simulations to rationalize experimental data, where mutants comprising the V571M substitution improve both transcriptional activity and affinity for aldosterone despite large distances between the mutated residue and the coactivator-binding surface and ligand-binding pocket, respectively. Our molecular dynamics simulations show that the V571M mutation modifies the coactivator-binding site defined by helices 3, 4, and 12, and that specific structural rearrangement of the coactivator-binding site correlates well with transactivation data. A similar reorganization of the coactivator-binding cleft is observed in crystallographic structures of the estrogen receptor in the presence of coactivator peptide, compared with structures without peptide, indicating that induced fit for coactivator binding is a general phenomenon for nuclear receptors. These results suggest that the V571M substitution facilitates recruitment of coactivator protein by promotion of a conformational substate reducing the energetic penalty for the induced fit of the receptor-coactivator complex. Furthermore, our simulations of V571M mutants showed reduced fluctuations of residues lining the ligand-binding pocket. This indicates that a reduction of the entropic cost for ligand binding may explain the increased affinity of V571M mutants for certain ligands.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  GR

Ligands:   Dexamethasone  |  17β-Estradiol  |  Progesterone

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