Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

Harada, Shusaku; Hiromori, Youhei; Nakamura, Shota; Kawahara, Kazuki; Fukakusa, Shunsuke; Maruno, Takahiro; Noda, Masanori; Uchiyama, Susumu; Fukui, Kiichi; Nishikawa, Junichi; Nagase, Hisamitsu; Kobayashi, Yuji; Yoshida, Takuya; Ohkubo, Tadayasu; Nakanishi, Tsuyoshi

doi:https://doi.org/10.1038/srep08520

Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

Harada, Shusaku; Hiromori, Youhei; Nakamura, Shota et al.

Scientific Reports, 2014, 5, 8520

Number of Access:2,121（2025-08-14 03:54 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/79034

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Title	Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds
Creator	CreatorName Harada, Shusaku
	NRID 1000060515956 1000060515956 CreatorName Hiromori, Youhei
	NRID 1000090432434 1000090432434 ORCID 0000-0003-2058-5942 0000-0003-2058-5942 researchmap permalink nkmrshota nkmrshota Scopus Author ID 35315778200 35315778200 CreatorName Nakamura, Shota
	NRID 1000060585058 1000060585058 researchmap permalink 051619 051619 Scopus Author ID 9740512500 9740512500 CreatorName Kawahara, Kazuki
	CreatorName Fukakusa, Shunsuke
	NRID 1000060648351 1000060648351 CreatorName Maruno, Takahiro
	CreatorName Noda, Masanori
	NRID 1000090335381 1000090335381 ORCID 0000-0002-5181-179X 0000-0002-5181-179X researchmap permalink read0090387 read0090387 Scopus Author ID 35429790100 35429790100 CreatorName Uchiyama, Susumu
	NRID 1000000311770 1000000311770 researchmap permalink read0068600 read0068600 CreatorName Fukui, Kiichi
	NRID 1000090218131 1000090218131 CreatorName Nishikawa, Junichi
	NRID 1000040141395 1000040141395 CreatorName Nagase, Hisamitsu
	NRID 1000020127228 1000020127228 CreatorName Kobayashi, Yuji
	NRID 1000000294116 1000000294116 ORCID 0000-0002-3491-9344 0000-0002-3491-9344 researchmap permalink takuya_yoshida takuya_yoshida Scopus Author ID 55252623800 55252623800 CreatorName Yoshida, Takuya
	NRID 1000090272997 1000090272997 researchmap permalink read0191274 read0191274 Scopus Author ID 7201618682 7201618682 CreatorName Ohkubo, Tadayasu
	NRID 1000050303988 1000050303988 CreatorName Nakanishi, Tsuyoshi
Description	Harada, S., Hiromori, Y., Nakamura, S. et al. Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds. Sci Rep 5, 8520 (2015). https://doi.org/10.1038/srep08520.
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.
Publisher	Nature Research
Source Title	Scientific Reports
Volume (Issue)	5
Page	8520
Date of Issued	2014-02-17
Language	English
Handle URL	https://hdl.handle.net/11094/79034
eISSN	20452322
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1038/srep08520
Relation.isIdenticalTo	PMID 25687586
Access Rights	open access
CopyRight	© 2015 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Scientific Reports. 2014, 5, p. 8520
DC.title	Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds
DC.creator	Harada, Shusaku
	Hiromori, Youhei
	Nakamura, Shota
	Kawahara, Kazuki
	Fukakusa, Shunsuke
	Maruno, Takahiro
	Noda, Masanori
	Uchiyama, Susumu
	Fukui, Kiichi
	Nishikawa, Junichi
	Nagase, Hisamitsu
	Kobayashi, Yuji
	Yoshida, Takuya
	Ohkubo, Tadayasu
	Nakanishi, Tsuyoshi
DC.publisher	Nature Research
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2014-02-17
DC.identifier	https://doi.org/10.1038/srep08520
DC.description	Harada, S., Hiromori, Y., Nakamura, S. et al. Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds. Sci Rep 5, 8520 (2015). https://doi.org/10.1038/srep08520.
DCTERMS.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.
DC.rights	© 2015 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	79034
citation_title	Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds
citation_author	Harada, Shusaku
	Hiromori, Youhei
	Nakamura, Shota
	Kawahara, Kazuki
	Fukakusa, Shunsuke
	Maruno, Takahiro
	Noda, Masanori
	Uchiyama, Susumu
	Fukui, Kiichi
	Nishikawa, Junichi
	Nagase, Hisamitsu
	Kobayashi, Yuji
	Yoshida, Takuya
	Ohkubo, Tadayasu
	Nakanishi, Tsuyoshi
citation_publisher	Nature Research
citation_language	English
citation_date	2014-02-17
citation_journal_title	Scientific Reports
citation_volume	5
citation_firstpage	8520
citation_doi	https://doi.org/10.1038/srep08520
citation_pmid	25687586
citation_public_url	https://hdl.handle.net/11094/79034

Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

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