A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors.
Partial, selective activation of nuclear receptors is a central issue in molecular endocrinology but only partly understood. Using LXRs as an example, we show here that purely agonistic ligands can be clearly and quantitatively differentiated from partial agonists by the cofactor interactions they induce. Although a pure agonist induces a conformation that is incompatible with the binding of repressors, partial agonists such as GW3965 induce a state where the interaction not only with coactivators, but also corepressors is clearly enhanced over the unliganded state. The activities of the natural ligand 22(R)-hydroxycholesterol and of a novel quinazolinone ligand, LN6500 can be further differentiated from GW3965 and T0901317 by their weaker induction of coactivator binding. Using biochemical and cell-based assays, we show that the natural ligand of LXR is a comparably weak partial agonist. As predicted, we find that a change in the coactivator to corepressor ratio in the cell will affect NCoR recruiting compounds more dramatically than NCoR-dissociating compounds. Our data show how competitive binding of coactivators and corepressors can explain the tissue-specific behavior of partial agonists and open up new routes to a rational design of partial agonists for LXRs.
Albers
Michael
M
PheneX Pharmaceuticals AG, 67056 Ludwigshafen, Germany and Department of Vascular and Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
Blume
Beatrix
B
Schlueter
Thomas
T
Wright
Matthew B
MB
Kober
Ingo
I
Kremoser
Claus
C
Deuschle
Ulrich
U
Koegl
Manfred
M
D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D002474:Cell-Free System; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry; D008024:Ligands; D000071518:Liver X Receptors; D008956:Models, Chemical; D008968:Molecular Conformation; D057093:Orphan Nuclear Receptors; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011799:Quinazolines / Q000737:chemistry; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques
D001565:Benzoates; D001596:Benzylamines; D017931:DNA Primers; D004268:DNA-Binding Proteins; C473027:GW 3965; D006888:Hydroxycholesterols; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010455:Peptides; D011799:Quinazolines; D018160:Receptors, Cytoplasmic and Nuclear