title: Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds.
abstract: Organotin compounds such as triphenyltin (TPT) and tributyltin (TBT) act as endocrine disruptors through the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. We recently found that TPT is a particularly strong agonist of PPARγ. To elucidate the mechanism underlying organotin-dependent PPARγ activation, we here analyzed the interactions of PPARγ 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 PPARγ-LBD/TBT and PPARγ-LBD/TPT complexes were determined at 1.95 Å and 1.89 Å, 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 π-π interactions. Our findings elucidate the structural basis of PPARγ activation by TPT.
authors: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Shusaku
authors: S
authors: Harada
authors: 1] Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan [2] Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan.
authors: Youhei
authors: Y
authors: Hiromori
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Shota
authors: S
authors: Nakamura
authors: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Kazuki
authors: K
authors: Kawahara
authors: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Shunsuke
authors: S
authors: Fukakusa
authors: Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Takahiro
authors: T
authors: Maruno
authors: Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Masanori
authors: M
authors: Noda
authors: Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Susumu
authors: S
authors: Uchiyama
authors: Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Kiichi
authors: K
authors: Fukui
authors: Laboratory of Health Sciences, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's Univerasity, 11-68 Kyuban-cho, Koshien, Nishinomiya, Hyogo, 663-8179, Japan.
authors: Jun-ichi
authors: J
authors: Nishikawa
authors: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan.
authors: Hisamitsu
authors: H
authors: Nagase
authors: Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yuji
authors: Y
authors: Kobayashi
authors: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Takuya
authors: T
authors: Yoshida
authors: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Tadayasu
authors: T
authors: Ohkubo
authors: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan.
authors: Tsuyoshi
authors: T
authors: Nakanishi
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D052244:Endocrine Disruptors / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008958:Models, Molecular; D009154:Mutation; D009947:Organotin Compounds / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014220:Trialkyltin Compounds / Q000494:pharmacology
chemical_list: D052244:Endocrine Disruptors; D008024:Ligands; D009947:Organotin Compounds; D047495:PPAR gamma; D014220:Trialkyltin Compounds; C011559:tributyltin; C030665:triphenyltin