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PDBsum entry 3gyu

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protein ligands links
Transcription PDB id
3gyu
Jmol
Contents
Protein chain
242 a.a. *
Ligands
LYS-SER-LEU-LEU-
GLN-GLN-LEU-LEU-
THR-GLU
DL7
Waters ×141
* Residue conservation analysis
PDB id:
3gyu
Name: Transcription
Title: Nuclear receptor daf-12 from parasitic nematode strongyloides stercoralis in complex with its physiological ligand dafachronic acid delta 7
Structure: Nuclear hormone receptor of the steroid/thyroid hormone receptors superfamily. Chain: a. Fragment: ligand binding domain. Engineered: yes. Src1. Chain: b. Fragment: nuclear receptor binding motif 4. Engineered: yes
Source: Strongyloides stercoralis. Organism_taxid: 6248. Gene: daf-12. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes
Resolution:
2.40Å     R-factor:   0.212     R-free:   0.255
Authors: X.E.Zhou,Z.Wang,K.Suino-Powell,D.L.Motola,A.Conneely, C.Ogata,K.K.Sharma,R.J.Auchus,S.A.Kliewer,H.E.Xu, D.J.Mangelsdorf
Key ref:
Z.Wang et al. (2009). Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proc Natl Acad Sci U S A, 106, 9138-9143. PubMed id: 19497877 DOI: 10.1073/pnas.0904064106
Date:
05-Apr-09     Release date:   07-Jul-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9XZJ5  (Q9XZJ5_9BILA) -  Nuclear hormone receptor of the steroid/thyroid hormone receptors superfamily
Seq:
Struc:
 
Seq:
Struc:
753 a.a.
242 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     sequence-specific DNA binding transcription factor activity     2 terms  

 

 
DOI no: 10.1073/pnas.0904064106 Proc Natl Acad Sci U S A 106:9138-9143 (2009)
PubMed id: 19497877  
 
 
Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes.
Z.Wang, X.E.Zhou, D.L.Motola, X.Gao, K.Suino-Powell, A.Conneely, C.Ogata, K.K.Sharma, R.J.Auchus, J.B.Lok, J.M.Hawdon, S.A.Kliewer, H.E.Xu, D.J.Mangelsdorf.
 
  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.
 
  Selected figure(s)  
 
Figure 1.
Conserved nuclear receptor signaling pathway controls dauer/iL3 diapause. (A) Schematic for signaling pathways that control dauer/iL3 diapause. The chemical structures for dafachronic acid ligands for DAF-12 are also shown. (B) Sequence similarities of DAF-12 homologues in parasitic nematodes. DAF-12 aa positions in the partial A. ceylanicum and N. americanus cDNA clones were assigned according to their homologous positions in A. caninum.
Figure 4.
DAF-12 activation induces iL3 recovery. (A and B) Dafachronic acids stimulate resumption of feeding in iL3 of A. caninum, (n = 250–1,200) (A), and S. stercoralis, n = 725–1,081 (B). (C) Dafachronic acids stimulate ASP secretion by A. caninum iL3 larvae. (D) Effects of PI3-kinase and P450 inhibitors on Δ7-DA induced feeding in A. caninum iL3 larvae (n = 100–407). S+G, 10% canine serum plus 15 mM GSM (A, C, and D) or 5 mM GSH (B); LY, PI3-kinase inhibitor LY249002; Kc, P450 inhibitor ketoconazole; *, P < 0.001; **, P < 0.0001; n.s., not significant; χ^2 2-tailed test, all compared with vehicle treatment unless indicated. Experiments were repeated 2 times (D) or 4 times (A and B) with similar results.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20592728 G.Bento, A.Ogawa, and R.J.Sommer (2010).
Co-option of the hormone-signalling module dafachronic acid-DAF-12 in nematode evolution.
  Nature, 466, 494-497.  
19796644 M.Hu, J.B.Lok, N.Ranjit, H.C.Massey, P.W.Sternberg, and R.B.Gasser (2010).
Structural and functional characterisation of the fork head transcription factor-encoding gene, Hc-daf-16, from the parasitic nematode Haemonchus contortus (Strongylida).
  Int J Parasitol, 40, 405-415.  
20876095 P.Nair, and D.J.Mangelsdorf (2010).
Profile of David J. Mangelsdorf.
  Proc Natl Acad Sci U S A, 107, 17463-17465.  
20135027 R.Martin, E.V.Entchev, T.V.Kurzchalia, and H.J.Knölker (2010).
Steroid hormones controlling the life cycle of the nematode Caenorhabditis elegans: stereoselective synthesis and biology.
  Org Biomol Chem, 8, 739-750.  
19965501 A.Ogawa, and R.J.Sommer (2009).
Strategies to get arrested.
  Science, 326, 944-945.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.