ecdysone receptor

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.{{cite journal | vauthors = Riddiford LM, Cherbas P, Truman JW | title = Ecdysone receptors and their biological actions | journal = Vitam. Horm. | volume = 60 | pages = 1–73 | year = 2000 | pmid = 11037621 | doi = 10.1016/S0083-6729(00)60016-X| series = Vitamins & Hormones | isbn = 978-0-12-709860-9 }} This in turn leads to the activation of many other genes, as evidenced by puffing of polytene chromosomes at over a hundred sites. Ultimately the activation cascade causes physiological changes that result in ecdysis (moulting). The temporal expression of ecdysone receptor within neural stem cells mediates temporal patterning and neural diversity.{{cite journal | vauthors = Syed MH, Mark B, Doe CQ | title = Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity | journal = eLife | volume = 6 | page = e26287 | date = April 2017 | pmid = 28394252 | doi = 10.7554/eLife.26287 | pmc=5403213 | doi-access = free }}{{cite book | editor-first1 = Sarjeet S. | editor-last1 = Gill | editor-last2 = Gilbert | editor-first2 = Lawrence I. | editor-first3 = Kostas | editor-last3 = Iatrou | vauthors = Henrich VC | title = Comprehensive molecular insect science | url = https://archive.org/details/comprehensivemol00gill | url-access = limited | publisher = Elsevier | location = Amsterdam | year = 2005 | pages = [https://archive.org/details/comprehensivemol00gill/page/n258 243]–285 | isbn = 978-0-444-51516-2 | chapter = The ecdysteroid receptor }}

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. Based on sequence homology considerations,{{cite journal | vauthors = Hayward DC, Bastiani MJ, Trueman JW, Truman JW, Riddiford LM, Ball EE | title = The sequence of Locusta RXR, homologous to Drosophila Ultraspiracle, and its evolutionary implications | journal = Dev. Genes Evol. | volume = 209 | issue = 9 | pages = 564–71 |date=September 1999 | pmid = 10502114 | doi = 10.1007/s004270050290| s2cid = 8703952 }} 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).{{cite journal | vauthors = Koelle MR, Talbot WS, Segraves WA, Bender MT, Cherbas P, Hogness DS | title = The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily | journal = Cell | volume = 67 | issue = 1 | pages = 59–77 |date=October 1991 | pmid = 1913820 | doi = 10.1016/0092-8674(91)90572-G| s2cid = 6805386 }} 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.{{cite journal | vauthors = Bourguet W, Germain P, Gronemeyer H | title = Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications | journal = Trends Pharmacol. Sci. | volume = 21 | issue = 10 | pages = 381–8 |date=October 2000 | pmid = 11050318 | doi = 10.1016/S0165-6147(00)01548-0}} 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.{{cite journal | vauthors = Clayton GM, Peak-Chew SY, Evans RM, Schwabe JW | title = The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 4 | pages = 1549–54 |date=February 2001 | pmid = 11171988 | pmc = 29294 | doi = 10.1073/pnas.041611298 | doi-access = free }}

X-ray crystal structures have been determined for several heterodimeric DNA-binding domains{{cite journal | vauthors = Devarakonda S, Harp JM, Kim Y, Ozyhar A, Rastinejad F | title = Structure of the heterodimeric ecdysone receptor DNA-binding complex | journal = EMBO J. | volume = 22 | issue = 21 | pages = 5827–40 |date=November 2003 | pmid = 14592980 | pmc = 275426 | doi = 10.1093/emboj/cdg569 }} and ligand-binding domains from ecdysone receptors.

Ecdysone receptors have two main fields of application:

• Gene switches - ecdysone receptor-controlled transgenes for controlled gene expression in scientific research, agriculture, and medicine.{{cite journal | vauthors = Palli SR, Hormann RE, Schlattner U, Lezzi M | title = Ecdysteroid receptors and their applications in agriculture and medicine | journal = Vitam. Horm. | volume = 73 | pages = 59–100 | year = 2005 | pmid = 16399408 | doi = 10.1016/S0083-6729(05)73003-X | series = Vitamins & Hormones | isbn = 0-12-709873-9 }}
• Insecticides - Diacylhydrazines, although not ecdysteroids, are agonists of lepidopteran ecdysone receptors and are used as caterpillar-selective larvicides.{{cite journal | vauthors = Dhadialla TS, Carlson GR, Le DP | title = New insecticides with ecdysteroidal and juvenile hormone activity | journal = Annu. Rev. Entomol. | volume = 43 | pages = 545–69 | year = 1998 | pmid = 9444757 | doi = 10.1146/annurev.ento.43.1.545 }}{{cite book | editor = Sarjeet S. Gill | editor2 = Gilbert, Lawrence I. | editor3 = Kostas Iatrou | vauthors = Dhadialla TS, Retnakaran A, Smagghe G | title = Comprehensive molecular insect science | publisher = Elsevier | location = Amsterdam | year = 2005 | pages = [https://archive.org/details/comprehensivemol00gill/page/n70 55]–115 | isbn = 0-444-51516-X | url =https://archive.org/details/comprehensivemol00gill| url-access = limited | chapter = Insect growth- and development-disrupting insecticides }} They are insect growth regulators and are in general environmentally benign.

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• 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.
• [http://www.dowagro.com/au/prod/mimic.htm Mimic] insecticide, and associated [https://web.archive.org/web/20080205201323/http://www.apvma.gov.au/publications/prssteb.shtml regulatory information] (for Australia).

Category:Insect developmental biology

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