title: 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.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhi
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Motola
authors.forename: Verena
authors.initials: V
authors.lastname: Gelmedin
authors.forename: John
authors.initials: J
authors.lastname: Hawdon
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000722:Ancylostoma / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000724:Ancylostomiasis / Q000378:metabolism / Q000628:therapy; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002782:Cholestenes / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015801:Helminth Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008322:Mammals; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein
chemical_list: D001647:Bile Acids and Salts; D002782:Cholestenes; D015801:Helminth Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C514718:cholestenoic acid