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PDBsum entry 1r20

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protein ligands Protein-protein interface(s) links
Hormone/growth factor receptor PDB id
1r20
Jmol
Contents
Protein chains
239 a.a. *
228 a.a. *
Ligands
EPH
HWG
Waters ×11
* Residue conservation analysis
PDB id:
1r20
Name: Hormone/growth factor receptor
Title: Crystal structure of the ligand-binding domains of the heterodimer ecr/usp bound to the synthetic agonist byi06830
Structure: Ultraspiracle protein. Chain: a. Engineered: yes. Ecdysone receptor. Chain: d. Engineered: yes
Source: Heliothis virescens. Tobacco budworm. Organism_taxid: 7102. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
3.00Å     R-factor:   0.244     R-free:   0.289
Authors: I.M.L.Billas,T.Iwema,J.M.Garnier,A.Mitschler,N.Rochel, D.Moras,Structural Proteomics In Europe (Spine)
Key ref:
I.M.Billas et al. (2003). Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor. Nature, 426, 91-96. PubMed id: 14595375 DOI: 10.1038/nature02112
Date:
25-Sep-03     Release date:   18-Nov-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q7SIF6  (Q7SIF6_HELVI) -  Gene regulation protein
Seq:
Struc:
264 a.a.
239 a.a.
Protein chain
Pfam   ArchSchema ?
O18473  (ECR_HELVI) -  Ecdysone receptor
Seq:
Struc:
 
Seq:
Struc:
576 a.a.
228 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   4 terms 
  Biochemical function     protein binding     7 terms  

 

 
DOI no: 10.1038/nature02112 Nature 426:91-96 (2003)
PubMed id: 14595375  
 
 
Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor.
I.M.Billas, T.Iwema, J.M.Garnier, A.Mitschler, N.Rochel, D.Moras.
 
  ABSTRACT  
 
The ecdysteroid hormones coordinate the major stages of insect development, notably moulting and metamorphosis, by binding to the ecdysone receptor (EcR); a ligand-inducible nuclear transcription factor. To bind either ligand or DNA, EcR must form a heterodimer with ultraspiracle (USP), the homologue of retinoid-X receptor. Here we report the crystal structures of the ligand-binding domains of the moth Heliothis virescens EcR-USP heterodimer in complex with the ecdysteroid ponasterone A and with a non-steroidal, lepidopteran-specific agonist BYI06830 used in agrochemical pest control. The two structures of EcR-USP emphasize the universality of heterodimerization as a general mechanism common to both vertebrates and invertebrates. Comparison of the EcR structures in complex with steroidal and non-steroidal ligands reveals radically different and only partially overlapping ligand-binding pockets that could not be predicted by molecular modelling and docking studies. These findings offer new perspectives for the design of insect-specific, environmentally safe insecticides. The concept of a ligand-dependent binding pocket in EcR provides an insight into the moulding of nuclear receptors to their ligand, and has potential applications for human nuclear receptors.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: The two structures of the ligand-binding domains of EcR-USP. a, b, Overall structure of the EcR-USP heterodimers in complex with the steroid hormone ponA (a) and the non-steroidal ligand BYI06830 (b). Helices H12 are shown as red cylinders. For USP, the missing loop connecting H5 to the -sheet is shown by a blue dashed line going close to the EcR H9-H10 loop, as suggested by the discontinuous electron density. The EcR ligands and the phospholipid in USP are shown in stick representation with carbon coloured in white, oxygen in red and nitrogen in blue. c, Ribbon diagram showing the superimposition of the ponA- and BYI06830-bound EcR-LBD structures. The view is restricted to the region differing the most between the two EcR-LBD structures encompassing H2, H6, H7 and the -sheet. The ponA-bound EcR-LBD is shown in yellow with ponA in magenta and the BYI06830-bound EcR-LBD in green with BYI06830 in blue. The two residues discussed in the text, F397 and Y403, are shown in yellow for the ponA-bound EcR-LBD and in red for the BYI06830-bound EcR-LBD. d, Surface representations of the ponA-bound EcR-LBD coloured according to the r.m.s. deviations calculated residue by residue between the ponA- and the BYI06830-bound EcR-LBDs. The scale ranges from 0 (white) to 7.5 ┼ (red). The two views are related by a 180░ rotation around the vertical axis.
Figure 2.
Figure 2: The LBDs of EcR complexed to a steroidal and a non-steroidal ligand exhibit different and only partially overlapping ligand-binding cavities. a, Stereoview of the two ligand-binding cavities of EcR-LBD, together with their respective ligand. The view is identical to that of Fig. 1a, b. The ponA-bound EcR cavity is shown in light orange and the BYI06830-bound EcR cavity in blue. The ligands are shown as stick models with ponA in orange and BYI06830 in blue. b, Superimposition of ponA and 1 ,25-dihydroxyvitamin D3 bound to their cognate receptor. The ponA-bound EcR-LBD and the vitamin D-bound VDR-LBD were superimposed using Lsq-man28. c, Superimposition of the steroidal and non-steroidal EcR ligands as bound to the EcR-LBD. Atom colouring is red for oxygen, blue for nitrogen, yellow for carbon in ponA and grey for carbon in vitamin D and in BYI06830.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 426, 91-96) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20231890 G.Tzertzinis, A.L.Egaña, S.R.Palli, M.Robinson-Rechavi, C.R.Gissendanner, C.Liu, T.R.Unnasch, and C.V.Maina (2010).
Molecular evidence for a functional ecdysone signaling system in Brugia malayi.
  PLoS Negl Trop Dis, 4, e625.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
20482650 O.Christiaens, M.Iga, R.A.Velarde, P.Rougé, and G.Smagghe (2010).
Halloween genes and nuclear receptors in ecdysteroid biosynthesis and signalling in the pea aphid.
  Insect Mol Biol, 19, 187-200.  
20069627 T.Soin, E.De Geyter, H.Mosallanejad, M.Iga, D.Martín, S.Ozaki, S.Kitsuda, T.Harada, H.Miyagawa, D.Stefanou, G.Kotzia, R.Efrose, V.Labropoulou, D.Geelen, K.Iatrou, Y.Nakagawa, C.R.Janssen, G.Smagghe, and L.Swevers (2010).
Assessment of species specificity of moulting accelerating compounds in Lepidoptera: comparison of activity between Bombyx mori and Spodoptera littoralis by in vitro reporter and in vivo toxicity assays.
  Pest Manag Sci, 66, 526-535.  
20672340 T.Soin, L.Swevers, G.Kotzia, K.Iatrou, C.R.Janssen, P.Rougé, T.Harada, Y.Nakagawa, and G.Smagghe (2010).
Comparison of the activity of non-steroidal ecdysone agonists between dipteran and lepidopteran insects, using cell-based EcR reporter assays.
  Pest Manag Sci, 66, 1215-1229.  
21152046 Y.Sato, N.Ramalanjaona, T.Huet, N.Potier, J.Osz, P.Antony, C.Peluso-Iltis, P.Poussin-Courmontagne, E.Ennifar, Y.Mély, A.Dejaegere, D.Moras, and N.Rochel (2010).
The "Phantom Effect" of the Rexinoid LG100754: structural and functional insights.
  PLoS One, 5, e15119.
PDB code: 3a9e
19490110 J.M.Beatty, G.Smagghe, T.Ogura, Y.Nakagawa, M.Spindler-Barth, and V.C.Henrich (2009).
Properties of ecdysteroid receptors from diverse insect species in a heterologous cell culture system--a basis for screening novel insecticidal candidates.
  FEBS J, 276, 3087-3098.  
19243223 K.I.Pardee, X.Xu, J.Reinking, A.Schuetz, A.Dong, S.Liu, R.Zhang, J.Tiefenbach, G.Lajoie, A.N.Plotnikov, A.Botchkarev, H.M.Krause, and A.Edwards (2009).
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.
  PLoS Biol, 7, e43.
PDB code: 3cqv
19065574 S.Lapenna, L.Dinan, J.Friz, A.J.Hopfinger, J.Liu, and R.E.Hormann (2009).
Semi-synthetic ecdysteroids as gene-switch actuators: synthesis, structure-activity relationships, and prospective ADME properties.
  ChemMedChem, 4, 55-68.  
19416074 T.C.Terwilliger, D.Stuart, and S.Yokoyama (2009).
Lessons from structural genomics.
  Annu Rev Biophys, 38, 371-383.  
19126866 T.Iwema, A.Chaumot, R.A.Studer, M.Robinson-Rechavi, I.M.Billas, D.Moras, V.Laudet, and F.Bonneton (2009).
Structural and evolutionary innovation of the heterodimerization interface between USP and the ecdysone receptor ECR in insects.
  Mol Biol Evol, 26, 753-768.  
19796154 Y.Nakagawa, and V.C.Henrich (2009).
Arthropod nuclear receptors and their role in molting.
  FEBS J, 276, 6128-6157.  
18354783 H.Esengil, and J.K.Chen (2008).
Gene regulation technologies in zebrafish.
  Mol Biosyst, 4, 300-308.  
18160712 K.Suino-Powell, Y.Xu, C.Zhang, Y.G.Tao, W.D.Tolbert, S.S.Simons, and H.E.Xu (2008).
Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.
  Mol Cell Biol, 28, 1915-1923.
PDB code: 3bqd
19021756 S.Lapenna, J.Friz, A.Barlow, S.R.Palli, L.Dinan, and R.E.Hormann (2008).
Ecdysteroid ligand-receptor selectivity--exploring trends to design orthogonal gene switches.
  FEBS J, 275, 5785-5809.  
18391212 S.M.Soisson, G.Parthasarathy, A.D.Adams, S.Sahoo, A.Sitlani, C.Sparrow, J.Cui, and J.W.Becker (2008).
Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation.
  Proc Natl Acad Sci U S A, 105, 5337-5342.
PDB code: 3bej
18384377 V.S.Tavva, S.R.Palli, R.D.Dinkins, and G.B.Collins (2008).
Improvement of a monopartite ecdysone receptor gene switch and demonstration of its utility in regulation of transgene expression in plants.
  FEBS J, 275, 2161-2176.  
18937503 Y.Chen, J.Jakoncic, J.Wang, X.Zheng, N.Carpino, and N.Nassar (2008).
Structural and functional characterization of the c-terminal domain of the ecdysteroid phosphate phosphatase from bombyx mori reveals a new enzymatic activity.
  Biochemistry, 47, 12135-12145.
PDB code: 3c7t
17848566 C.Browning, E.Martin, C.Loch, J.M.Wurtz, D.Moras, R.H.Stote, A.P.Dejaegere, and I.M.Billas (2007).
Critical role of desolvation in the binding of 20-hydroxyecdysone to the ecdysone receptor.
  J Biol Chem, 282, 32924-32934.
PDB code: 2r40
17188557 J.B.Biggins, and J.T.Koh (2007).
Chemical biology of steroid and nuclear hormone receptors.
  Curr Opin Chem Biol, 11, 99.  
17426125 M.Jakób, R.Ko┼éodziejczyk, M.Or┼éowski, S.Krzywda, A.Kowalska, J.Dutko-Gwó┼║d┼║, T.Gwó┼║d┼║, M.Kochman, M.Jaskólski, and A.Ozyhar (2007).
Novel DNA-binding element within the C-terminal extension of the nuclear receptor DNA-binding domain.
  Nucleic Acids Res, 35, 2705-2718.
PDB code: 2han
17703321 M.Nemoto, and K.Hara (2007).
Ecdysone receptor expression in developing and adult mushroom bodies of the ant Camponotus japonicus.
  Dev Genes Evol, 217, 619-627.  
18028192 Y.Nakagawa, A.Sakai, F.Magata, T.Ogura, M.Miyashita, and H.Miyagawa (2007).
Molecular cloning of the ecdysone receptor and the retinoid X receptor from the scorpion Liocheles australasiae.
  FEBS J, 274, 6191-6203.  
16249087 C.E.Wheelock, Y.Nakagawa, T.Harada, N.Oikawa, M.Akamatsu, G.Smagghe, D.Stefanou, K.Iatrou, and L.Swevers (2006).
High-throughput screening of ecdysone agonists using a reporter gene assay followed by 3-D QSAR analysis of the molting hormonal activity.
  Bioorg Med Chem, 14, 1143-1159.  
16756554 F.Bonneton, F.G.Brunet, J.Kathirithamby, and V.Laudet (2006).
The rapid divergence of the ecdysone receptor is a synapomorphy for Mecopterida that clarifies the Strepsiptera problem.
  Insect Mol Biol, 15, 351-362.  
17201771 J.Beatty, T.Fauth, J.L.Callender, M.Spindler-Barth, and V.C.Henrich (2006).
Analysis of transcriptional activity mediated by Drosophila melanogaster ecdysone receptor isoforms in a heterologous cell culture system.
  Insect Mol Biol, 15, 785-795.  
15822096 B.Greb-Markiewicz, T.Fauth, and M.Spindler-Barth (2005).
Ligand binding is without effect on complex formation of the ligand binding domain of the ecdysone receptor (EcR).
  Arch Insect Biochem Physiol, 59, 1.  
16011476 D.M.Ruden, M.De Luca, M.D.Garfinkel, K.L.Bynum, and X.Lu (2005).
Drosophila nutrigenomics can provide clues to human gene-nutrient interactions.
  Annu Rev Nutr, 25, 499-522.  
15809296 J.A.Carmichael, M.C.Lawrence, L.D.Graham, P.A.Pilling, V.C.Epa, L.Noyce, G.Lovrecz, D.A.Winkler, A.Pawlak-Skrzecz, R.E.Eaton, G.N.Hannan, and R.J.Hill (2005).
The X-ray structure of a hemipteran ecdysone receptor ligand-binding domain: comparison with a lepidopteran ecdysone receptor ligand-binding domain and implications for insecticide design.
  J Biol Chem, 280, 22258-22269.
PDB code: 1z5x
15803199 K.King-Jones, and C.S.Thummel (2005).
Nuclear receptors--a perspective from Drosophila.
  Nat Rev Genet, 6, 311-323.  
15642259 M.A.Holmes, W.Paulsene, X.Jide, C.Ratledge, and R.K.Strong (2005).
Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration.
  Structure, 13, 29-41.
PDB codes: 1x71 1x89 1x8u
15756700 S.R.Palli, C.M.Tice, V.M.Margam, and A.M.Clark (2005).
Biochemical mode of action and differential activity of new ecdysone agonists against mosquitoes and moths.
  Arch Insect Biochem Physiol, 58, 234-242.  
16302963 S.R.Palli, M.Z.Kapitskaya, and D.W.Potter (2005).
The influence of heterodimer partner ultraspiracle/retinoid X receptor on the function of ecdysone receptor.
  FEBS J, 272, 5979-5990.  
16098194 T.Ogura, C.Minakuchi, Y.Nakagawa, G.Smagghe, and H.Miyagawa (2005).
Molecular cloning, expression analysis and functional confirmation of ecdysone receptor and ultraspiracle from the Colorado potato beetle Leptinotarsa decemlineata.
  FEBS J, 272, 4114-4128.  
15897460 W.Wang, C.Zhang, A.Marimuthu, H.I.Krupka, M.Tabrizizad, R.Shelloe, U.Mehra, K.Eng, H.Nguyen, C.Settachatgul, B.Powell, M.V.Milburn, and B.L.West (2005).
The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1.
  Proc Natl Acad Sci U S A, 102, 7505-7510.
PDB codes: 1zdt 1zdu
15161930 H.Greschik, R.Flaig, J.P.Renaud, and D.Moras (2004).
Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity.
  J Biol Chem, 279, 33639-33646.
PDB codes: 1s9p 1s9q 1tfc 1vjb
15520817 H.Gronemeyer, J.A.Gustafsson, and V.Laudet (2004).
Principles for modulation of the nuclear receptor superfamily.
  Nat Rev Drug Discov, 3, 950-964.  
15107428 M.B.Kumar, D.W.Potter, R.E.Hormann, A.Edwards, C.M.Tice, H.C.Smith, M.A.Dipietro, M.Polley, M.Lawless, P.R.Wolohan, D.R.Kethidi, and S.R.Palli (2004).
Highly flexible ligand binding pocket of ecdysone receptor: a single amino acid change leads to discrimination between two groups of nonsteroidal ecdysone agonists.
  J Biol Chem, 279, 27211-27218.  
15271205 R.Petersen Brown, M.R.Berenbaum, and M.A.Schuler (2004).
Transcription of a lepidopteran cytochrome P450 promoter is modulated by multiple elements in its 5' UTR and repressed by 20-hydroxyecdysone.
  Insect Mol Biol, 13, 337-347.  
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. Where a reference describes a PDB structure, the PDB code is shown on the right.