Ecdysone receptor

protein
Name = Ecdysone receptor protein, "Drosophila melanogaster"
caption =


width =
HGNCid =
Symbol = EcR
AltSymbols = EcRH, NR1H1
EntrezGene = 35540
OMIM =
RefSeq =
UniProt = P34021
PDB = 1R0O
ECnumber =
Chromosome =
Arm =
Band =
LocusSupplementaryData =

protein
Name = Ultraspiracle protein, "Drosophila melanogaster"
caption =


width =
HGNCid =
Symbol = USP
AltSymbols = Cf1, NR2B4
EntrezGene = 31165
OMIM =
RefSeq =
UniProt = P20153
PDB = 1HG4
ECnumber =
Chromosome =
Arm =
Band = 3
LocusSupplementaryData =

The ecdysone receptor is a nuclear hormone receptor found in arthropods, where it controls development and contributes to other processes such as reproduction. The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). It binds, and is activated by, ecdysteroids. Insect ecdysone receptors are currently better characterized than those from other arthropods, and mimics of ecdysteroids are used commercially as caterpillar-selective insecticides.

Purpose

Pulses of 20-hydroxyecdysone occur during insect development, whereupon this hormone binds to the ecdysone receptor, a ligand-activated transcription factor found in the nuclei of insect cells. [Riddiford, L.M., Cherbas, P., Truman, J.W. (2000) Ecdysone receptors and their biological actions. "Vitam. Horm." 60, 1-73.] This in turn leads to the activation of many other genes, as evidenced by chromosomal puffing at over a hundred sites. Ultimately the activation cascade causes physiological changes that result in ecdysis (moulting). [Henrich, V.C. (2005) The ecdysteroid receptor, in "Comprehensive Molecular Insect Science", Gilbert, L.I., Iatrou, K., Gill, S.S., eds. Elsevier, online edition, Chapter 3.5 (pp.243-285). ISBN 978-0-444-51516-2]

= Structure and function =

The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). These nuclear hormone receptor proteins are the insect orthologs of the mammalian farnesoid X receptor (FXR) and retinoid X receptor (RXR) proteins, respectively. Indeed, based on sequence homology considerations [Hayward, D.C., Bastiani, M.J., Trueman, J.W., Truman, J.W., Riddiford, L.M., Ball, E.E. (1999) The sequence of Locusta RXR, homologous to Drosophila Ultraspiracle, and its evolutionary implications. "Dev Genes Evol." 209, 564-71.] , some researchers reserve the term USP for the EcR partner from lepidopteran and dipteran insects, and use RXR in all other instances.

EcR and USP share the multi-domain architecture common to all nuclear hormone receptors, namely an N-terminal transcriptional activation domain (A/B domain), a DNA-binding domain (C domain, highly conserved between receptors), a linker region (D region), a ligand-binding domain (E domain, moderately conserved), and in some cases a distinct C-terminal extension (F-domain). [Koelle, M.R., Talbot, W.S., Segraves, W.A., Bender, M.T., Cherbas, P., Hogness, D.S. (1991). The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily. "Cell" 67, 59-77.] The DNA-binding domains of EcR and USP recognise specific short sequences in DNA, and mediate the binding of the heterodimer to these ecdysone response elements (ECREs) in the promoters of ecdysone-responsive genes.

The ecdysteroid-binding pocket is located in the ligand-binding domain of the EcR subunit, but EcR must be dimerised with a USP (or with an RXR) for high-affinity ligand binding to occur. In such circumstances, the binding of an agonist ligand triggers a conformational change in the C-terminal part of the EcR ligand-binding domain that leads to transcriptional activation of genes under ECRE control [Bourguet, W., Germain, P., Gronemeyer, H. (2000) Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. "Trends Pharmacol. Sci." 21, 381-8.] . There is also a ligand-binding pocket in the corresponding domain of USP. Its natural ligand remains uncertain, and USPs appear to be locked permanently in an inactive conformation. [Clayton, G.M., Peak-Chew, S.Y., Evans, R.M., Schwabe, J.W. (2001) The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation. "Proc. Natl. Acad. Sci. USA" 98, 1549-54.]

X-ray crystal structures have been determined for several heterodimeric DNA-binding domains [Devarakonda, S., Harp, J.M., Kim, Y., Ozyhar, A., Rastinejad, F. (2003) Structure of the heterodimeric ecdysone receptor DNA-binding complex. "EMBO J." 22, 5827-40.] and ligand-binding domains [Billas, I.M., Iwema, T., Garnier, J.M., Mitschler, A., Rochel, N., and Moras, D. (2003). Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor. "Nature" 426, 91-96.] [Carmichael, J.A., Lawrence, M.C., Graham, L.D., Pilling, P.A., Epa, V.C., Noyce, L., Lovrecz, G., Winkler, D.A., Pawlak-Skrzecz, A., Eaton, R.E., Hannan, G.N., and Hill, R.J. (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: 22258-69.] from ecdysone receptors.

Commercial interest and applications

Ecdysone receptors have two main fields of application:

*Gene switches - ecdysone receptor-controlled transgenes for controlled gene expression in scientific research, agriculture, and medicine. [Palli, S.R., Hormann, R.E., Schlattner, U., Lezzi, M. (2005) Ecdysteroid receptors and their applications in agriculture and medicine. "Vitam. Horm." 73, 59-100.] The last category includes potential use in gene therapy. [Graham, L.D. (2002) Ecdysone-controlled expression of transgenes. "Expert Opin. Biol. Ther." 2, 525-536.]

*Insecticides - the development of selective insect growth regulators for use as environmentally benign insecticides. Although dibenzoylhydrazine compounds are not ecdysteroids, many are agonists of lepidopteran ecdysone receptors and are used as caterpillar-selective larvicides. [Dhadialla, T.S., Carlson, G.R., Le, D.P. (1998) New insecticides with ecdysteroidal and juvenile hormone activity. "Ann. Rev. Entomol." 43, 545-569.] [Dhadialla, T.S., Retnakaran, A., Smagghe, G. (2005) Insect growth- and development-disrupting insecticides, in "Comprehensive Molecular Insect Science", Gilbert, L.I., Iatrou, K., Gill, S.S., eds. Elsevier, online edition, Chapter 6.3 (pp.55-115). ISBN 978-0-444-51516-2]

References

External links

"PDB representative structures of ecdysone receptor ligand binding domains:"

[http://www.pdb.org/pdb/explore/explore.do?structureId=1R1K 1R1K] , ligand-binding domain heterodimer of "Heliothis viresecens" in complex with an ecdysteroid; [http://www.pdb.org/pdb/explore/explore.do?structureId=1R20 1R20] , the same heterodimer in complex with a dibenzoylhydrazine agonist.

"Insecticides:"

[http://www.dowagro.com/au/prod/mimic.htm Mimic] insecticide, and associated [http://www.apvma.gov.au/publications/prssteb.shtml regulatory information] (for Australia).