4E2J

X-Ray Crystal Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with mometasone furoate and TIF-2 coactivator fragment

Summary for 4E2J

• Entry DOI: 10.2210/pdb4e2j/pdb
• Descriptor: Ancestral Glucocorticoid Receptor 2, Nuclear receptor coactivator 2, GLYCEROL, ... (6 entities in total)
• Functional Keywords: nuclear receptor ligand binding domain, glucocorticoid receptor, steroid binding protein, hormone-hormone activator complex, hormone/hormone activator
• Biological source: synthetic construct; More
• Cellular location: Nucleus: Q15596
• Total number of polymer chains: 4
• Total formula weight: 61751.29

Authors

Kohn, J.A.,Deshpande, K.,Ortlund, E.A. (deposition date: 2012-03-08, release date: 2012-03-28, Last modification date: 2023-09-13)

Primary citation

Kohn, J.A.,Deshpande, K.,Ortlund, E.A.
Deciphering Modern Glucocorticoid Cross-pharmacology Using Ancestral Corticosteroid Receptors.
J.Biol.Chem., 287:16267-16275, 2012

PubMed Abstract: Steroid receptors (SRs) are the largest family of metazoan transcription factors and control genes involved in development, endocrine signaling, reproduction, immunity, and cancer. The entire hormone receptor system is driven by a molecular switch triggered by the binding of small lipophilic ligands. This makes the SRs ideal pharmaceutical targets, yet even the best clinically approved synthetic steroidal agonists are prone to cross-reactivity and off-target pharmacology. The mechanism underlying this promiscuity is derived from the fact that SRs share common structural features derived from their evolutionary relationship. More often than not, rational attempts to probe SR drug selectivity via mutagenesis fail even when high quality structural and functional data are available due to the fact that important mutations often result in nonfunctional receptors. This highlights the fact that SRs suffer from instability, preventing in-depth mutational analysis and hampering crystallization of key receptor-ligand complexes. We have taken a unique approach to address this problem by using a resurrected ancestral protein to determine the structure of a previously intractable complex and identified the structural mechanisms that confer activation and selectivity for a widely used glucocorticoid, mometasone furoate. Moreover, we have identified a single residue located outside of the ligand-binding pocket that controls mometasone furoate antagonism versus agonism in the human mineralocorticoid receptor.

PubMed: 22437833
DOI: 10.1074/jbc.M112.346411

Experimental method

X-RAY DIFFRACTION (2.5 Å)