TY - JOUR
T1 - The estrogen receptor
T2 - A structure-based approach to the design of new specific hormone-receptor combinations
AU - Tedesco, Rosanna
AU - Thomas, James A.
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
N1 - Funding Information:
We are grateful for support of this research through Grants from the National Institutes of health (PHS 5R37 DK15556 (to J.A.K.) PHS 5R37 CA18119 (to B.S.K.) and a predoctoral traineeship 5T32 GM07283 (to J.A.T.)). We thank Kathryn E. Carlson for performing binding assays and Roderick Hubbard and Ashley Pike for helpful discussions on ER structures. NMR spectra were obtained in the Varian Oxford Instrument Center for Excellence NMR Laboratory. Funding for this instrumentation was provided in part from the W.M. Keck Foundation and the National Science Foundation (NSF CHE 96-10502). Mass spectra were obtained on instruments supported by grants from the National Institute of General Medical Sciences (GM 27019), the National Institute of Health (RR 01575), and the National Science Foundation (PCM 8121494).
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Estrogen receptor
KW - Hormone specificity
KW - Receptor specificity reengineering
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U2 - 10.1016/S1074-5521(01)00006-0
DO - 10.1016/S1074-5521(01)00006-0
M3 - Article
C2 - 11306352
AN - SCOPUS:0035068096
SN - 1074-5521
VL - 8
SP - 277
EP - 287
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 3
ER -