1s9p

From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 1s9p, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

crystal structure of the ligand-binding domain of the estrogen-related receptor gamma in complex with diethylstilbestrol

Overview

The estrogen-related receptor (ERR) gamma behaves as a constitutive, activator of transcription. Although no natural ligand is known, ERRgamma, is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol, and the selective ER modulator 4-hydroxytamoxifen but does not, significantly respond to estradiol or raloxifene. Here we report the, crystal structures of the ERRgamma ligand binding domain (LBD) complexed, with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to, ERRgamma results in a rotation of the side chain of Phe-435 that partially, fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the, "activation helix" (helix 12) from the agonist position observed in the, absence of ligand. In contrast to the complexes of the ERalpha LBD with, 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERRgamma, does not occupy the coactivator groove but appears to be completely, dissociated from the LBD body. Comparison of the ligand-bound LBDs of, ERRgamma and ERalpha reveals small but significant differences in the, architecture of the ligand binding pockets that result in a slightly, shifted binding position of diethylstilbestrol and a small rotation of, 4-hydroxytamoxifen in the cavity of ERRgamma relative to ERalpha. Our, results provide detailed molecular insight into the conformational changes, occurring upon binding of synthetic antagonists to the constitutive orphan, receptor ERRgamma and reveal structural differences with ERs that explain, why ERRgamma does not bind estradiol or raloxifene and will help to design, new selective antagonists.

About this Structure

1S9P is a Single protein structure of sequence from Mus musculus with DES as ligand. Full crystallographic information is available from OCA.

Reference

Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity., Greschik H, Flaig R, Renaud JP, Moras D, J Biol Chem. 2004 Aug 6;279(32):33639-46. Epub 2004 May 24. PMID:15161930

Page seeded by OCA on Wed Nov 21 02:13:02 2007