Evidence for Ligand-independent Transcriptional Activation of the Human Estrogen-related Receptor α (ERRα): CRYSTAL STRUCTURE OF ERRα LIGAND BINDING DOMAIN IN COMPLEX WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR COACTIVATOR-1α

Joerg Kallen,Jean-Marc Schlaeppi,Francis Bitsch,Ireos Filipuzzi,Alain Schilb,Virginie Riou,Alexander Graham,Andre Strauss,Martin Geiser,Brigitte Fournier

doi:10.1074/jbc.m407999200

Joerg Kallen, Jean-Marc Schlaeppi + Show 8 more

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https://doi.org/10.1074/jbc.m407999200

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Abstract

The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor alpha (ERRalpha, NR3B1) complexed with a coactivator peptide from peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) reveals a transcriptionally active conformation in the absence of a ligand. This is the first x-ray structure of ERRalpha LBD, solved to a resolution of 2.5 A, and the first structure of a PGC-1alpha complex. The putative ligand binding pocket (LBP) of ERRalpha is almost completely occupied by side chains, in particular with the bulky side chain of Phe328 (corresponding to Ala272 in ERRgamma and Ala350 in estrogen receptor alpha). Therefore, a ligand of a size equivalent to more than approximately 4 carbon atoms could only bind in the LBP, if ERRalpha 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 ERRalpha. The interactions of PGC-1alpha with ERRalpha 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-1alpha peptide containing this nuclear box motif from the L3 site binds ERRalpha 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-1alpha are present.

Highlights

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
The recent elucidation of the crystal structures of ERR␥ ligand binding domain (LBD) bound to an SRC-1 peptide [16], as well as of ERR␥ LBD bound to the antagonists DES and 4-hydroxytamoxifen [17], suggests that the ERRs assume the conformation of ligand-activated nuclear receptors (NRs) in the absence of ligand and that agonist ligands may not be required
We show that the first x-ray structure of ERR␣ LBD and the first x-ray structure of a PGC-1␣ form a complex

Summary

Introduction

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. The recent elucidation of the crystal structures of ERR␥ ligand binding domain (LBD) bound to an SRC-1 peptide [16], as well as of ERR␥ LBD bound to the antagonists DES and 4-hydroxytamoxifen [17], suggests that the ERRs assume the conformation of ligand-activated nuclear receptors (NRs) in the absence of ligand and that agonist ligands may not be required (but rather that ERRs might be ligand-inactivated instead). These findings in general raised the question of how the activity of ERRs is regulated in vivo

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