Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes.
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.
Wang
Zhu
Z
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Zhou
X Edward
XE
Motola
Daniel L
DL
Gao
Xin
X
Suino-Powell
Kelly
K
Conneely
Aoife
A
Ogata
Craig
C
Sharma
Kamalesh K
KK
Auchus
Richard J
RJ
Lok
James B
JB
Hawdon
John M
JM
Kliewer
Steven A
SA
Xu
H Eric
HE
Mangelsdorf
David J
DJ
D000722:Ancylostoma / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002782:Cholestenes / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007814:Larva; D008958:Models, Molecular; D017221:Necator americanus / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D017206:Strongylida Infections / Q000188:drug therapy / Q000469:parasitology*; D017171:Strongyloides stercoralis / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; C410905:DAF-12 protein, C elegans; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; C533800:dafachronic acid