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Volume 272, Number 29, Issue of July 18, 1997 pp. 18267-18272
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Mutational Analysis Reveals That All-trans-retinoic acid, 9-cis-Retinoic acid, and Antagonist Interact with Distinct Binding Determinants of RARalpha

(Received for publication, December 4, 1996, and in revised form, April 11, 1997)

Siegfried Keidel , François P. Y. Lamour and Christian M. Apfel

From the Preclinical Research, Department of Infectious Diseases, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland

Retinoids exert their pleiotropic effects on cell differentiation and proliferation through specific nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Two biologically highly active natural retinoids have been identified, all-trans-retinoic acid (t-RA) and 9-cis-retinoic acid (9-cis-RA). The RXRs exclusively bind 9-cis-RA, whereas the RARs bind both isomers of RA with comparable affinity. Recently published results suggest that RARs have the same binding site for t-RA and 9-cis-RA but with different determinants (1-3). Antagonist binding on RARalpha has been suggested to induce distinct conformational changes in comparison with agonist binding. To elucidate the region minimally required for efficient binding of agonist (t-RA and 9-cis-RA) and antagonist Ro 41-5253 to the RARalpha , we generated N- and C-terminally truncated mutants of the receptor. Characterization of these deletion mutant proteins using protease mapping and ligand binding experiments revealed that different parts of the ligand-binding domain are necessary for t-RA, 9-cis-RA, and antagonist binding. Three distinct regions of the ligand-binding domain of the human retinoic acid receptor-alpha are required for binding of t-RA (RARalpha 187-402), 9-cis-RA (RARalpha 188-409), and the antagonist Ro 41-5253 (RARalpha 226-414).


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 Mol. Endocrinol.Home page
B. Farboud and M. L. Privalsky
Retinoic Acid Receptor-{alpha} Is Stabilized in a Repressive State by Its C-Terminal, Isotype-Specific F Domain
Mol. Endocrinol., December 1, 2004; 18(12): 2839 - 2853.
[Abstract] [Full Text] [PDF]


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Copyright © 1997 by the American Society for Biochemistry and Molecular Biology.