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Titolo:
Selective regulation of gene expression by an orthogonal estrogen receptor-ligand pair created by polar-group exchange
Autore:
Shi, YH; Koh, JT;
Indirizzi:
Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA Univ Delaware Newark DE USA 19716 pt Chem & Biochem, Newark, DE 19716 USA
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 5, volume: 8, anno: 2001,
pagine: 501 - 510
SICI:
1074-5521(200105)8:5<501:SROGEB>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
SITE-SPECIFIC RECOMBINATION; THYROID-HORMONE RECEPTORS; RETINOID-X-RECEPTOR; BINDING DOMAIN; MAMMALIAN-CELLS; NUCLEAR-RECEPTOR; CRYSTAL-STRUCTURE; TRANSCRIPTIONAL ACTIVATION; INDUCIBLE EXPRESSION; AMINO-ACIDS;
Keywords:
gene expression regulation; estrogen receptor; polar-group exchange; synthetic ligand;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
71
Recensione:
Indirizzi per estratti:
Indirizzo: Koh, JT Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA Univ Delaware Newark DE USA 19716 & Biochem, Newark, DE 19716 USA
Citazione:
Y.H. Shi e J.T. Koh, "Selective regulation of gene expression by an orthogonal estrogen receptor-ligand pair created by polar-group exchange", CHEM BIOL, 8(5), 2001, pp. 501-510

Abstract

Background: The nuclear and steroid hormone receptors Function as ligand-dependent transcriptional regulators in eukaryotes. Hormone receptors have been engineered to selectively respond to synthetic ligands and used as remote regulators of gene expression for the study of gene function and as potential regulators of gene therapies. Results: In this work, a new ligand-receptor engineering strategy called 'polar-group exchange is used to create a mutant form of the estrogen receptor, ER(Glu353 --> Ala), which lacks a carboxyl group critical for high-affinity binding of estradiol. bur is able to transactivate in response to nanomolar concentrations of a carboxylate-functionalized estrogen analog, ES8. ES8 activates ER(Glu353 --> Ala) at concentrations that do not appreciably activate the 'wild-type receptor ER(wt). Two similar carboxylate-functionalized ligands, ES6 and ES7, do not induce transactivation function. Similar selectivities are observed in ligand-binding assays in vitro, which Follow the trends predicted by molecular modeling. Conclusions: Polar-group exchange is an effective strategy for rationally engineering ligand-receptor pairs. The ER(E353A)/ES8 ligand-receptor pair should constitute a unique and functionally orthogonal ligand-dependent transcriptional regulator. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/21 alle ore 01:36:26