3GYT

Nuclear receptor DAF-12 from parasitic nematode Strongyloides stercoralis in complex with its physiological ligand dafachronic acid delta 4

Summary for 3GYT

• Entry DOI: 10.2210/pdb3gyt/pdb
• Related: 3GYU
• Descriptor: Nuclear hormone receptor of the steroid/thyroid hormone receptors superfamily, SRC1, (14beta,17alpha,25R)-3-oxocholest-4-en-26-oic acid, ... (4 entities in total)
• Functional Keywords: nuclear receptor, ligand binding domain, dafachronic acid, src1, nematode, strongyloides stercoralis, dna-binding, metal-binding, nucleus, receptor, transcription, transcription regulation, zinc, zinc-finger
• Biological source: Strongyloides stercoralis
• Total number of polymer chains: 2
• Total formula weight: 29713.19

Authors

Zhou, X.E.,Wang, Z.,Suino-Powell, K.,Motola, D.L.,Conneely, A.,Ogata, C.,Sharma, K.K.,Auchus, R.J.,Kliewer, S.A.,Xu, H.E.,Mangelsdorf, D.J. (deposition date: 2009-04-05, release date: 2009-07-07, Last modification date: 2024-02-21)

Primary citation

Wang, Z.,Zhou, X.E.,Motola, D.L.,Gao, X.,Suino-Powell, K.,Conneely, A.,Ogata, C.,Sharma, K.K.,Auchus, R.J.,Lok, J.B.,Hawdon, J.M.,Kliewer, S.A.,Xu, H.E.,Mangelsdorf, D.J.
Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes.
Proc.Natl.Acad.Sci.USA, 106:9138-9143, 2009

PubMed Abstract: Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over 1 billion people. The molecular mechanisms governing infection are poorly understood. Here, we report that an evolutionarily conserved nuclear hormone receptor signaling pathway governs development of the stage 3 infective larvae (iL3) in several nematode parasites, including Strongyloides stercoralis, Ancylostoma spp., and Necator americanus. As in the free-living Caenorhabditis elegans, steroid hormone-like dafachronic acids induced recovery of the dauer-like iL3 in parasitic nematodes by activating orthologs of the nuclear receptor DAF-12. Moreover, administration of dafachronic acid markedly reduced the pathogenic iL3 population in S. stercoralis, indicating the potential use of DAF-12 ligands to treat disseminated strongyloidiasis. To understand the pharmacology of targeting DAF-12, we solved the 3-dimensional structure of the S. stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes.

PubMed: 19497877
DOI: 10.1073/pnas.0904064106

Experimental method

X-RAY DIFFRACTION (2.4 Å)