2E2R

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

Summary for 2E2R

• Entry DOI: 10.2210/pdb2e2r/pdb
• Descriptor: Estrogen-related receptor gamma, 4,4'-PROPANE-2,2-DIYLDIPHENOL, GLYCEROL, ... (4 entities in total)
• Functional Keywords: err gamma, bpa, nuclear receptor, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (Probable): P62508
• Total number of polymer chains: 1
• Total formula weight: 28115.70

Authors

Matsushima, A.,Kakuta, Y.,Teramoto, T.,Koshiba, T.,Kimura, M.,Shimohigashi, Y. (deposition date: 2006-11-16, release date: 2007-09-11, Last modification date: 2023-10-25)

Primary citation

Matsushima, A.,Kakuta, Y.,Teramoto, T.,Koshiba, T.,Liu, X.,Okada, H.,Tokunaga, T.,Kawabata, S.,Kimura, M.,Shimohigashi, Y.
Structural Evidence for Endocrine Disruptor Bisphenol A Binding to Human Nuclear Receptor ERR{gamma}
J.Biochem.(Tokyo), 142:517-524, 2007

PubMed Abstract: Many lines of evidence reveal that bisphenol A (BPA) functions at very low doses as an endocrine disruptor. The human estrogen-related receptor gamma (ERR gamma) behaves as a constitutive activator of transcription, although the endogenous ligand is unknown. We have recently demonstrated that BPA binds strongly to ERR gamma (K(D) = 5.5 nM), but not to the estrogen receptor (ER). BPA preserves the ERR gamma's basal constitutive activity, and protects the selective ER modulator 4-hydroxytamoxifen from its deactivation of ERR gamma. In order to shed light on a molecular mechanism, we carried out the X-ray analysis of crystal structure of the ERR gamma ligand-binding domain (LBD) complexed with BPA. BPA binds to the receptor cavity without changing any internal structures of the pocket of the ERR gamma-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 forms complexes with the endocrine disruptor, providing detailed molecular insight into the interaction features.

PubMed: 17761695
DOI: 10.1093/jb/mvm158

Experimental method

X-RAY DIFFRACTION (1.6 Å)