3up0 | pdb_00003up0

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

spinqualitylabelsall models 3up0, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3up0 is a 4 chain structure with sequence from Ancylostoma ceylanicum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: D7S Related: 3up3 Gene: daf-12 (Ancylostoma ceylanicum) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Function [NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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