2e2r

From Proteopedia

Revision as of 10:01, 23 January 2008

Crystal structure of human estrogen-related receptor gamma ligand binding domain complex with bisphenol A

Overview

Many lines of evidence reveal that bisphenol A (BPA) functions at very low, doses as an endocrine disruptor. The human estrogen-related receptor gamma, (ERRgamma) behaves as a constitutive activator of transcription, although, the endogenous ligand is unknown. We have recently demonstrated that BPA, binds strongly to ERRgamma (K(D) = 5.5 nM), but not to the estrogen, receptor (ER). BPA preserves the ERRgamma's basal constitutive activity, and protects the selective ER modulator 4-ydroxytamoxifen from its, deactivation of ERRgamma. In order to shed light on a molecular mechanism, we carried out the X-ray analysis of crystal structure of the ERRgamma, ligand binding domain (LBD) complexed with BPA. BPA binds to the receptor, cavity without changing any internal structures of the pocket of the, ERRgamma-LBD apo form. The hydrogen bonds of two phenol-hydroxyl groups, one with both Glu275 and Arg316, the other with Asn346, anchor BPA in the, pocket, and surrounding hydrophobic bonds, especially with Tyr326, complete BPA's strong binding. Maintaining the "activation helix" (helix, 12) in an active conformation would as a result preserve receptor, constitutive activity. Our results present the first evidence that the, nuclear receptor complexes with the endocrine disruptor, providing, detailed molecular insight into the interaction features.

About this Structure

2E2R is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.

Reference

Structural Evidence for Endocrine Disruptor Bisphenol A Binding to Human Nuclear Receptor ERR{gamma}, Matsushima A, Kakuta Y, Teramoto T, Koshiba T, Liu X, Okada H, Tokunaga T, Kawabata SI, Kimura M, Shimohigashi Y, J Biochem (Tokyo). 2007 Aug 30;. PMID:17761695

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