Structural basis for PPAR? 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 ? (PPAR?) signaling pathway. We recently found that TPT is a particularly strong agonist of PPAR?. To elucidate the mechanism underlying organotin-dependent PPAR? activation, we here analyzed the interactions of PPAR? 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?-LBD/TBT and PPAR?-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 ?-? interactions. Our findings elucidate the structural basis of PPAR? activation by TPT.

SUBMITTER: Harada S 

PROVIDER: S-EPMC4330522 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature