Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists.
Retinoic acid receptors (RARs) are ligand-dependent transcription factors that control a plethora of physiological processes. RARs exert their functions by regulating gene networks controlling cell growth, differentiation, survival, and death. Uncovering the molecular details by which synthetic ligands direct specificity and functionality of nuclear receptors is key to rational drug development. Here we define the molecular basis for (E)-4-[2-[5,6-Dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl]ethen-1-yl]benzoic acid (BMS204,493) acting as the inverse pan-RAR agonist and define 4-[5,6-Dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido]benzoic acid (BMS195,614) as the neutral RARalpha-selective antagonist. We reveal the details of the differential coregulator interactions imposed on the receptor by the ligands and show that the anchoring of H12 is fundamentally distinct in the presence of the two ligands, thus accounting for the observed effects on coactivator and corepressor interactions. These ligands will facilitate studies on the role of the constitutive activity of RARs, particularly of the tumor suppressor RARbeta, whose specific functions relative to other RARs have remained elusive.
Germain
Pierre
P
Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Gaudon
Claudine
C
Pogenberg
Vivian
V
Sanglier
Sarah
S
Van Dorsselaer
Alain
A
Royer
Catherine A
CA
Lazar
Mitchell A
MA
Bourguet
William
W
Gronemeyer
Hinrich
H
D010129:4-Aminobenzoic Acid / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054314:Drug Inverse Agonism; D006367:HeLa Cells; D006801:Humans; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D062366:para-Aminobenzoates
C542472:4-(2-(5,6-dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl)ethen-1-yl)benzoic acid; C542473:4-(5,6-dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido)benzoic acid; D001565:Benzoates; D050505:Mutant Proteins; D011804:Quinolines; D018168:Receptors, Retinoic Acid; D047490:Retinoid X Receptor alpha; D013267:Stilbenes; D062366:para-Aminobenzoates; D010129:4-Aminobenzoic Acid