A Characteristic Back Support Structure in the Bisphenol A-Binding Pocket in the Human Nuclear Receptor ERR[gamma]

• Published in: PloS one 2014-06, Vol.9 (6)
• Main Authors: Liu, Xiaohui, Matsushima, Ayami, Shimohigashi, Miki, Shimohigashi, Yasuyuki
• Format: Article
• Language: English
• Subjects: Analysis; Bisphenol-A; Chemical properties; Glycine; Phenols (Class of compounds); Physiological aspects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101252

The endocrine disruptor bisphenol A (BPA) affects various genes and hormones even at merely physiological levels. We recently demonstrated that BPA binds strongly to human nuclear receptor estrogen-related receptor (ERR) [gamma] and that the phenol-A group of BPA is in a receptacle pocket with essential amino acid residues to provide structural support at the backside. This led BPA to bind to ERR[gamma] in an induced-fit-type binding mode, for example, with a rotated motion of Val313 to support the Tyr326-binding site. A similar binding mechanism appears to occur at the binding site of the BPA phenol-B ring. X-ray crystal analysis of the ERR[gamma]-ligand-binding domain/BPA complex suggested that the ERR[gamma] receptor residues Leu342, Leu345, Asn346, and Ile349 function as intrinsic binding sites of the BPA phenol-B, whereas Leu265, Leu268, Ile310, Val313, Leu324, Tyr330, Lys430, Ala431, and His434 work as structural elements to assist these binding sites. In the present study, by evaluating the mutant receptors replaced by a series of amino acids, we demonstrated that a finely assembled structural network indeed exists around the two adjacent Leu.sup.342 -Asn.sup.346 and Leu.sup.345 -Ile.sup.349 ridges on the same [alpha]-helix 7 (H7), constructing a part of the binding pocket structure with back support residues for the BPA phenol-B ring. The results reveal that the double-layer binding sites, namely, the ordinary ligand binding sites and their back support residues, substantiate the strong binding of BPA to ERR[gamma]. When ERR[gamma]-Asn346 was replaced by the corresponding Gly and Tyr in ERR[alpha] and ERR[beta], respectively, the binding affinity of BPA and even 4-hydroxytamxifen (4-OHT) is much reduced. Asn346 was found to be one of the residues that make ERR[gamma] to be exclusive to BPA.