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

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 alpha (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. (C) 2001 Elsevier Science Ltd. All rights reserved.