title: Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma.
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.
authors.affiliation: Laboratory of Structure-Function Biochemistry, Department of Chemistry, Research-Education Centre of Risk Science, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Ayami
authors.initials: A
authors.lastname: Matsushima
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Kakuta
authors.forename: Takamasa
authors.initials: T
authors.lastname: Teramoto
authors.forename: Takumi
authors.initials: T
authors.lastname: Koshiba
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okada
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Tokunaga
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Kawabata
authors.forename: Makoto
authors.initials: M
authors.lastname: Kimura
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shimohigashi
mesh_terms: D001559:Benzhydryl Compounds; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D010636:Phenols / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D010636:Phenols; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; C490917:ESRRG protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds