Selective regulation of gene expression by an orthogonal estrogen receptor–ligand pair created by polar-group exchange

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