The estrogen receptor: A structure-based approach to the design of new specific hormone-receptor combinations

Rosanna Tedesco, James A. Thomas, Benita S. Katzenellenbogen, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Background: The specificity of hormone action arises from complementary steric and electronic interactions between a hormonal ligand and its cognate receptor. An analysis of such key ligand-receptor contact sites, often delineated by mutational mapping and X-ray crystallographic studies, can suggest ways in which hormone-receptor specificity might be altered. Results: We have altered the hormonal specificity of the estrogen receptor α (ER) by making 'coordinated' changes in the A-ring of the ligand estradiol and in the A-ring binding subpocket of ER. These changes were designed to maintain a favorable interaction when both E and ER are changed, but to disfavor interaction when only E or ER is changed. We have evaluated several of these altered ligand and receptor pairs in quantitative ligand binding and reporter gene assays. Conclusions: In best cases, the new interaction is sufficiently favorable and orthogonal so as to represent the creation of a new hormone specificity, which might be useful in the regulation of transgene activity.

Original languageEnglish (US)
Pages (from-to)277-287
Number of pages11
JournalChemistry and Biology
Volume8
Issue number3
DOIs
StatePublished - Apr 25 2001

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Keywords

  • Estrogen receptor
  • Hormone specificity
  • Receptor specificity reengineering

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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