The steroid/thyroid hormone receptor superfamily are important mediators of signal transduction in higher eukaryotes. These soluble nuclear receptors are activated as transcription mediators by binding to specific small molecule hormones; examples of hormone ligands include estrogen, thyroid, retinoic acid, and glucocorticoid. In general, a significant receptor conformational change is induced upon hormone binding. Synthetic antagonists that bind to the receptors and block hormone action are useful as drugs or biochemical probes. To date, no synthetic antagonists have been developed for the thyroid receptor. We are interested in understanding the structural basis of agonist and antagonist action for this family of receptors and are approaching the problem by combining modern synthetic chemistry with structural biology. We have developed a combinatorial solid-phase strategy for preparing a library of hydroxystilbene analogs as non-steroidal estrogen agonists. A series of analogs was identified from the library which show agonist activity in a cell culture system and estrogen receptor binding in vitro. In another project, we are using protein crystallography results to guide the design of thyroid receptor antagonist. The crystal structure of the thyroid receptor has recently been solved in Robert Fletterick's laboratory and the structure shows several novel hormone-receptor interactions that may guide the design of antagonists.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-21
Application #
6280261
Study Section
Project Start
1998-07-01
Project End
1999-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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