HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 32, 23231-23239, August 10, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/32/23231    most recent M703337200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kallen, J. Articles by Fournier, B. Search for Related Content PubMed PubMed Citation Articles by Kallen, J. Articles by Fournier, B. Social Bookmarking                      What's this?

Crystal Structure of Human Estrogen-related Receptor in Complex with a Synthetic Inverse Agonist Reveals Its Novel Molecular Mechanism^*

From the Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland

Inverse agonists of the constitutively active human estrogen-related receptor (ERR, NR3B1) are of potential interest for several disease indications (e.g. breast cancer, metabolic diseases, or osteoporosis). ERR is constitutively active, because its ligand binding pocket (LBP) is practically filled with side chains (in particular with Phe³²⁸, which is replaced by Ala in ERR and ERR). We present here the crystal structure of the ligand binding domain of ERR (containing the mutation C325S) in complex with the inverse agonist cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound 1a), to a resolution of 2.3Å_. The structure reveals the dramatic multiple conformational changes in the LBP, which create the necessary space for the ligand. As a consequence of the new side chain conformation of Phe³²⁸ (on helix H3), Phe⁵¹⁰(H12) has to move away, and thus the activation helix H12 is displaced from its agonist position. This is a novel mechanism of H12 inactivation, different from ERR, estrogen receptor (ER) , and ER. H12 binds (with a surprising binding mode) in the coactivator groove of its ligand binding domain, at a similar place as a coactivator peptide. This is in contrast to ERR but resembles the situation for ER (raloxifene or 4-hydroxytamoxifen complexes). Our results explain the novel molecular mechanism of an inverse agonist for ERR and provide the basis for rational drug design to obtain isotype-specific inverse agonists of this potential new drug target. Despite a practically filled LBP, the finding that a suitable ligand can induce an opening of the cavity also has broad implications for other orphan nuclear hormone receptors (e.g. the NGFI-B subfamily).

Received for publication, April 20, 2007 , and in revised form, June 6, 2007.

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

¹ To whom correspondence should be addressed. E-mail: Joerg.kallen{at}novartis.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Heck, J. Rom, V. Thewes, N. Becker, B. Blume, H. P. Sinn, U. Deuschle, C. Sohn, A. Schneeweiss, and P. Lichter Estrogen-Related Receptor {alpha} Expression and Function Is Associated with the Transcriptional Coregulator AIB1 in Breast Carcinoma Cancer Res., June 15, 2009; 69(12): 5186 - 5193. [Abstract] [Full Text] [PDF]

				M. J. Chisamore, H. A. Wilkinson, O. Flores, and J. D. Chen Estrogen-related receptor-{alpha} antagonist inhibits both estrogen receptor-positive and estrogen receptor-negative breast tumor growth in mouse xenografts Mol. Cancer Ther., March 1, 2009; 8(3): 672 - 681. [Abstract] [Full Text] [PDF]

				V. Giguere Transcriptional Control of Energy Homeostasis by the Estrogen-Related Receptors Endocr. Rev., October 1, 2008; 29(6): 677 - 696. [Abstract] [Full Text] [PDF]

				H. Greschik, M. Althage, R. Flaig, Y. Sato, V. Chavant, C. Peluso-Iltis, L. Choulier, P. Cronet, N. Rochel, R. Schule, et al. Communication between the ERR{alpha} Homodimer Interface and the PGC-1{alpha} Binding Surface via the Helix 8-9 Loop J. Biol. Chem., July 18, 2008; 283(29): 20220 - 20230. [Abstract] [Full Text] [PDF]