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Originally published In Press as doi:10.1074/jbc.M009870200 on February 6, 2001

J. Biol. Chem., Vol. 276, Issue 18, 15059-15065, May 4, 2001
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Crystal Structure of a Mutant hERalpha Ligand-binding Domain Reveals Key Structural Features for the Mechanism of Partial Agonism*

Monique Gangloff, Marc Ruff, Sylvia Eiler, Sylvie Duclaud, Jean Marie Wurtz, and Dino MorasDagger

From the Institut de Genetique et de Biologie Moleculaire et Cellulaire, Laboratoire de Biologie et de Génomique Structurales 1, rue Laurent Fries, BP 163 67404 Illkirch, France

The crystal structure of a triple cysteine to serine mutant ERalpha ligand-binding domain (LBD), complexed with estradiol, shows that despite the presence of a tightly bound agonist ligand, the protein exhibits an antagonist-like conformation, similar to that observed in raloxifen and 4-hydroxytamoxifen-bound structures. This mutated receptor binds estradiol with wild type affinity and displays transcriptional activity upon estradiol stimulation, but with limited potency (about 50%). This partial activity is efficiently repressed in antagonist competition assays. The comparison with available LBD structures reveals key features governing the positioning of helix H12 and highlights the importance of cysteine residues in promoting an active conformation. Furthermore the present study reveals a hydrogen bond network connecting ligand binding to protein trans conformation. These observations support a dynamic view of H12 positioning, where the control of the equilibrium between two stable locations determines the partial agonist character of a given ligand.

* This work was supported by funds from Schering AG and CNRS and by grants from the Ministère de la Recherche et de l'Enseignement Supérieur and the Association pour la Recherche sur le Cancer.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1QKT) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Dagger To whom correspondence should be addressed. Tel.: 33-388-65-3351; Fax: 33-388-65-3276; E-mail: moras@igbmc.u-strasbg.fr.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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