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Mol Cell Endocrinol. 1998 Apr 30;139(1-2):161-9.

Distinct modes of interaction of the retinoic acid receptor alpha with natural and synthetic retinoids.

Author information

1
INSERM U 459, Laboratoire de Biochimie Structurale, Faculté de Médecine Henri Warembourg, Lille, France.

Abstract

Retinoids regulate key cellular processes through their binding to their cognate nuclear receptors, RARs and RXRs. Synthetic ligands mimic most of their biological effects and alteration of their chemical structure confers selectivity for RAR isotypes alpha, beta or gamma. In this study, we have examined the contribution of a domain (L box) of hRARalpha located at the C-terminus of the ligand binding domain (LBD), between helices H11 and H12, to the ligand binding activity of this receptor. By site-directed mutagenesis, we demonstrate that, in the absence of the ligand-dependent activation domain 2 (AF2-AD), the receptor discriminates between classes of structurally distinct retinoids. This property was lost in the presence of the AF2-AD domain, evidencing major structural transitions in this part of the receptor. We propose that ligand binding occurs in two steps: first, the ligand interacts with the LBD in its opened, holo-receptor conformation in which the L box plays a crucial role in defining the ligand binding repertoire of hRARalpha; secondly, the LBD adopts its closed conformation in which the ligand interacts with the receptor mostly through its carboxylic moiety.

PMID:
9705084
DOI:
10.1016/s0303-7207(98)00065-3
[Indexed for MEDLINE]

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