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J. Biol. Chem., Vol. 279, Issue 47, 49330-49337, November 19, 2004
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(ERR)
LIGAND BINDING DOMAIN IN COMPLEX WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR COACTIVATOR-1*
From the
Protein Structure Unit, the ¶Biomolecules Production Unit, the ||Department of Analytical and Imaging Sciences, the **Department of Global Screening Operation, and the Department of Bone Metabolism, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland
The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor (ERR, NR3B1) complexed with a coactivator peptide from peroxisome proliferator-activated receptor coactivator-1 (PGC-1) reveals a transcriptionally active conformation in the absence of a ligand. This is the first x-ray structure of ERR LBD, solved to a resolution of 2.5 Å, and the first structure of a PGC-1 complex. The putative ligand binding pocket (LBP) of ERR is almost completely occupied by side chains, in particular with the bulky side chain of Phe328 (corresponding to Ala272 in ERR
and Ala350 in estrogen receptor ). Therefore, a ligand of a size equivalent to more than 
4 carbon atoms could only bind in the LBP, if ERR would undergo a major conformational change (in particular the ligand would displace H12 from its agonist position). The x-ray structure thus provides strong evidence for ligand-independent transcriptional activation by ERR. The interactions of PGC-1 with ERR also reveal for the first time the atomic details of how a coactivator peptide containing an inverted LXXLL motif (namely a LLXYL motif) binds to a LBD. In addition, we show that a PGC-1 peptide containing this nuclear box motif from the L3 site binds ERR LBD with a higher affinity than a peptide containing a steroid receptor coactivator-1 motif and that the affinity is further enhanced when all three leucine-rich regions of PGC-1 are present.
Received for publication, July 15, 2004 , and in revised form, August 25, 2004.
The atomic coordinates and structure factors (code 1XB7
* 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.
To whom correspondence may be addressed: Protein Structure Unit, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Tel.: 4161-324-5579; Fax: 4161-324-2686; E-mail: joerg.kallen{at}pharma.novartis.com. To whom correspondence may be addressed: Dept. of Bone Metabolism, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Tel.: 41-61-6964462; Fax: 41-61-6963849; E-mail: brigitte.fournier{at}pharma.novartis.com.
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