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Journal of Biochemistry Advance Access originally published online on August 30, 2007
Journal of Biochemistry 2007 142(4):517-524; doi:10.1093/jb/mvm158
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© 2007 The Japanese Biochemical Society.

Structural Evidence for Endocrine Disruptor Bisphenol A Binding to Human Nuclear Receptor ERR{gamma}

Ayami Matsushima1, Yoshimitsu Kakuta2, Takamasa Teramoto2, Takumi Koshiba3, Xiaohui Liu1, Hiroyuki Okada1, Takatoshi Tokunaga1, Shun-ichiro Kawabata3, Makoto Kimura2 and Yasuyuki Shimohigashi1,*

1Laboratory of Structure-Function Biochemistry, Department of Chemistry, Research-Education Centre of Risk Science, Faculty and Graduate School of Sciences; 2Laboratory of Biochemistry, Department of Agricultural Chemistry, Faculty and Graduate School of Agriculture; and 3Laboratory of Life Biochemistry, Department of Biological Science, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan

*To whom correspondence should be addressed. Tel: +81-92-642-2584; Fax: +81-92-642-2584; E-mail: shimoscc{at}mbox.nc.kyushu-u.ac.jp

Received May 30, 2007; Accepted July 25, 2007


  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} (KD = 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.

Key Words: binding assay, bisphenol A, estrogen-related receptor {gamma} (ERR{gamma}), nuclear receptor, X-ray crystal structure

Abbreviations: BPA, bisphenol A; CBB, Coomassie brilliant blue; CHAPS, 3-[3-(cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; DES, diethylstilbestrol; ER, estrogen receptor; ERR, estrogen-related receptor; ERE, estrogen response element; ERRE, ERR-response element; LBD, ligand-binding domain; MALDI-TOF, matrix-assisted laser desorption ionization time-of-flight; NR, nuclear receptor; 4-OHT, 4-hydroxytamoxifen; and PCR, polymerase chain reaction


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