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.
Tedesco
R
R
Department of Chemistry, University of Illinois, Urbana 61801, USA.
Thomas
J A
JA
Katzenellenbogen
B S
BS
Katzenellenbogen
J A
JA
D000818:Animals; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004967:Estrogens / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen