3UP3

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

3UP3 の概要

• エントリーDOI: 10.2210/pdb3up3/pdb
• 関連するPDBエントリー: 3UP0
• 分子名称: aceDAF-12, Nuclear receptor coactivator 2, (8alpha,10alpha,25S)-3-hydroxycholesta-3,5-dien-26-oic acid, ... (5 entities in total)
• 機能のキーワード: ligand binding domain, nematode, steroid binding protein-transcription complex, steroid binding protein/transcription
• 由来する生物種: Ancylostoma ceylanicum; 詳細
• 細胞内の位置: Nucleus: Q15596
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30238.62

構造登録者

Zhi, X.,Zhou, X.E.,Melcher, K.,Motola, D.L.,Gelmedin, V.,Hawdon, J.,Kliewer, S.A.,Mangelsdorf, D.J.,Xu, H.E. (登録日: 2011-11-17, 公開日: 2011-12-14, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.25 Å)