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Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.

ABSTRACT: Bile acid-like molecules named dafachronic acids (DAs) control the dauer formation program in Caenorhabditis elegans through the nuclear receptor DAF-12. This mechanism is conserved in parasitic nematodes to regulate their dauer-like infective larval stage, and as such, the DAF-12 ligand binding domain has been identified as an important therapeutic target in human parasitic hookworm species that infect more than 600 million people worldwide. Here, we report two x-ray crystal structures of the hookworm Ancylostoma ceylanicum DAF-12 ligand binding domain in complex with DA and cholestenoic acid (a bile acid-like metabolite), respectively. Structure analysis and functional studies reveal key residues responsible for species-specific ligand responses of DAF-12. Furthermore, DA binds to DAF-12 mechanistically and is structurally similar to bile acids binding to the mammalian bile acid receptor farnesoid X receptor. Activation of DAF-12 by cholestenoic acid and the cholestenoic acid complex structure suggest that bile acid-like signaling pathways have been conserved in nematodes and mammals. Together, these results reveal the molecular mechanism for the interplay between parasite and host, provide a structural framework for DAF-12 as a promising target in treating nematode parasitism, and provide insight into the evolution of gut parasite hormone-signaling pathways.

SUBMITTER: Zhi X

PROVIDER: S-EPMC3281614 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.

Zhi Xiaoyong X Zhou X Edward XE Melcher Karsten K Motola Daniel L DL Gelmedin Verena V Hawdon John J Kliewer Steven A SA Mangelsdorf David J DJ Xu H Eric HE

The Journal of biological chemistry 20111214 7

Bile acid-like molecules named dafachronic acids (DAs) control the dauer formation program in Caenorhabditis elegans through the nuclear receptor DAF-12. This mechanism is conserved in parasitic nematodes to regulate their dauer-like infective larval stage, and as such, the DAF-12 ligand binding domain has been identified as an important therapeutic target in human parasitic hookworm species that infect more than 600 million people worldwide. Here, we report two x-ray crystal structures of the h ...[more]

PMID: 22170062

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Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.

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Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.

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