3up3

Publication Abstract from PubMed

Bile acid-like molecules named dafachronic acids (DAs) control the dauer formation program in C. elegans through the nuclear receptor DAF-12. This mechanism is conserved in parasitic nematodes to regulate their dauer-like infective larvae stage and as such the DAF-12 ligand binding domain (LBD) 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 LBD 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 structurally similar to bile acids binding to the mammalian bile acid receptor FXR. 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.

Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes.,Zhi X, Zhou XE, Melcher K, Motola DL, Gelmedin V, Hawdon J, Kliewer SA, Mangelsdorf DJ, Xu HE J Biol Chem. 2011 Dec 21. PMID:22170062^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.