3UP0

Nuclear receptor DAF-12 from hookworm Ancylostoma ceylanicum in complex with (25S)-delta7-dafachronic acid

Summary for 3UP0

• Entry DOI: 10.2210/pdb3up0/pdb
• Related: 3UP3
• Descriptor: aceDAF-12, Nuclear receptor coactivator 2, (5beta,14beta,17alpha,25S)-3-oxocholest-7-en-26-oic acid, ... (4 entities in total)
• Functional Keywords: nematode, steroid binding protein-transcription complex, steroid binding protein/transcription
• Biological source: Ancylostoma ceylanicum; More
• Cellular location: Nucleus: Q15596
• Total number of polymer chains: 4
• Total formula weight: 59788.58

Authors

Zhi, X.,Zhou, X.E.,Melcher, K.,Motola, D.L.,Gelmedin, V.,Hawdon, J.,Kliewer, S.A.,Mangelsdorf, D.J.,Xu, H.E. (deposition date: 2011-11-17, release date: 2011-12-14, Last modification date: 2024-02-28)

Primary citation

Zhi, X.,Zhou, X.E.,Melcher, K.,Motola, D.L.,Gelmedin, V.,Hawdon, J.,Kliewer, S.A.,Mangelsdorf, D.J.,Xu, H.E.
Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes.
J.Biol.Chem., 287:4894-4903, 2012

PubMed 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.

PubMed: 22170062
DOI: 10.1074/jbc.M111.315242

Experimental method

X-RAY DIFFRACTION (1.6 Å)