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Summary: Rational discovery of novel nuclear hormone
receptor antagonists
Matthieu Schapira*
, Bruce M. Raaka
, Herbert H. Samuels
, and Ruben Abagyan*§
*Structural Biology, Skirball Institute of Biomolecular Medicine, and Division of Molecular Endocrinology, Departments of Medicine and Pharmacology,
New York University School of Medicine, 550 First Avenue, New York, NY 10016
Edited by Peter G. Schultz, The Scripps Research Institute, La Jolla, CA, and approved December 7, 1999 (received for review October 20, 1999)
Nuclear hormone receptors (NRs) are potential targets for thera-
peutic approaches to many clinical conditions, including cancer,
diabetes, and neurological diseases. The crystal structure of the
ligand binding domain of agonist-bound NRs enables the design of
compounds with agonist activity. However, with the exception of
the human estrogen receptor- , the lack of antagonist-bound
``inactive'' receptor structures hinders the rational design of re-
ceptor antagonists. In this study, we present a strategy for design-
ing such antagonists. We constructed a model of the inactive
conformation of human retinoic acid receptor- by using informa-
tion derived from antagonist-bound estrogen receptor- and ap-
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