Structural basis for PPAR gamma transactivation by endocrine-disrupting organotin compounds

作者：Harada Shusaku; Hiromori Youhei; Nakamura Shota; Kawahara Kazuki; Fukakusa Shunsuke; Maruno Takahiro; Noda Masanori; Uchiyama Susumu; Fukui Kiichi; Nishikawa Jun ichi; Nagase Hisamitsu; Kobayashi Yuji; Yoshida Takuya; Ohkubo Tadayasu; Nakanishi Tsuyoshi^*

来源：Scientific Reports, 2015, 5(1): 8520.

DOI：10.1038/srep08520

Organotin compounds such as triphenyltin (TPT) and tributyltin (TBT) act as endocrine disruptors through the peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling pathway. We recently found that TPT is a particularly strong agonist of PPAR gamma. To elucidate the mechanism underlying organotin-dependent PPAR gamma activation, we here analyzed the interactions of PPAR gamma ligand-binding domain (LBD) with TPT and TBT by using X-ray crystallography and mass spectroscopy in conjunction with cell-based activity assays. Crystal structures of PPAR gamma-LBD/TBT and PPAR gamma-LBD/TPT complexes were determined at 1.95 angstrom and 1.89 angstrom, respectively. Specific binding of organotins is achieved through non-covalent ionic interactions between the sulfur atom of Cys285 and the tin atom. Comparisons of the determined structures suggest that the strong activity of TPT arises through interactions with helix 12 of LBD primarily via pi-pi interactions. Our findings elucidate the structural basis of PPAR gamma activation by TPT.

• 出版日期2015-2-17