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

Xiaoyong Zhi, X. Edward Zhou, Karsten Melcher, Daniel L. Motola, Verena Gelmedin, John Hawdon, Steven A. Kliewer, David J. Mangelsdorf, H. Eric Xu

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4894-4903
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number7
DOIs
StatePublished - Feb 10 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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