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J. Biol. Chem., Vol. 282, Issue 45, 32924-32934, November 9, 2007

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Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor^*

Christopher Browning¹, Elyette Martin¹, Caroline Loch², Jean-Marie Wurtz, Dino Moras³, Roland H. Stote, Annick P. Dejaegere⁴, and Isabelle M. L. Billas

From the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département de Biologie et de Génomique Structurales, Illkirch, F-67400 France, INSERM, U596, Illkirch, F-67400 France, CNRS, UMR7104, Illkirch, F-67400 France, Université Louis Pasteur, Faculté des Sciences de la Vie, Strasbourg, F-67000 France, and the Laboratoire de Biophysicochimie Moléculaire, Institut de Chimie de Strasbourg, Université Louis Pasteur, F-67000 Strasbourg, France

The insect steroid hormone 20-hydroxyecdysone (20E) binds to its cognate nuclear receptor composed of the ecdysone receptor (EcR) and Ultraspiracle (USP) and triggers the main developmental transitions, in particular molting and metamorphosis. We present the crystal structure of the ligand-binding domains of EcR/USP in complex with 20E at 2.4Å resolution and compare it with published structures of EcR/USP bound to ponasterone A (ponA). ponA is essentially identical to 20E but lacks the 25-OH group of 20E. The structure of 20E-bound EcR indicates that an additional hydrogen bond is formed compared with the ponA-bound receptor, yet, paradoxically, ponA has a significantly higher affinity for EcR than 20E. Theoretical studies based on docking and free energy methods lead to a rationale for understanding the difference in binding affinities between 20E and ponA. Results of the calculations indicate that the favorable contribution from the extra H-bond made by 25-OH of 20E is counterbalanced by its larger desolvation cost compared with that of ponA. The contribution of 25-OH to the binding affinity is further compared with those of 20- and 22-OH groups. Ligands that lack the 20- or 22-OH group are indeed known to bind less favorably to EcR than 20E, an effect opposite to that observed for ponA. The results indicate that their respective contributions to receptor-ligand complex stability reside mostly in their different contributions to solvation/desolvation. Together, the data demonstrate the critical role of ligand desolvation in determining binding affinity, with general implications for the binding of hormones to their cognate nuclear receptors.

Received for publication, July 6, 2007 , and in revised form, September 7, 2007.

The atomic coordinates and structure factors (code 2R40) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The work was supported in part by Bayer CropScience, the Association pour la Recherche sur le Cancer, and European Commission SPINE2 Contract LSHG-CT-2006-031220 under the Integrated Programme "Quality of Life and Management of Living Ressources." This work was also supported by funds from the Ligue Contre le Cancer (to E. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S6 and Fig. S1.

¹ These authors contributed equally to this work.

² Present address: ZoBio BV, Einsteinweg 55, 2333 CC Leiden, The Netherlands.

³ To whom correspondence may be addressed: Dépt. de Biologie et de Génomique Structurales, IGBMC, 1, rue Laurent Fries, F-67400 Illkirch Cedex, France. Tel.: 33-3-88-65-32-20; Fax: 33-3-88-32-76; E-mail: moras{at}igbmc.u-strasbg.fr. ⁴ To whom correspondence may be addressed: Dépt. de Biologie et de Génomique Structurales, IGBMC, Ecole Supérieure de Biotechnologie de Strasbourg, Parc d'Innovation, Boulevard Sébastien Brant, BP 10413, F-67412 Illkirch Cedex, France. Tel.: 33-3-90-24-47-21; Fax: 33-3-90-24-47-18; E-mail: annick{at}igbmc.u-strasbg.fr.

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