The structural basis for the specificity of retinoid-X receptor-selective agonists: new insights into the role of helix H12.
Ligands that specifically target retinoid-X receptors (RXRs) are emerging as potentially powerful therapies for cancer, diabetes, and the lowering of circulatory cholesterol. To date, RXR has only been crystallized in the absence of ligand or with the promiscuous ligand 9-cis retinoic acid, which also activates retinoic acid receptors. Here we present the structure of hRXRbeta in complex with the RXR-specific agonist LG100268 (LG268). The structure clearly reveals why LG268 is specific for the RXR ligand binding pocket and will not activate retinoic acid receptors. Intriguingly, in the crystals, the C-terminal "activation" helix (AF-2/helix H12) is trapped in a novel position not seen in other nuclear receptor structures such that it does not cap the ligand binding cavity. Mammalian two-hybrid assays indicate that LG268 is unable to release co-repressors from RXR unless co-activators are also present. Together these findings suggest that RXR ligands may be inefficient at repositioning helix H12.
Love
James D
JD
Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
Gooch
John T
JT
Benko
Szilvia
S
Li
Chuan
C
Nagy
Laszlo
L
Chatterjee
V Krishna K
VK
Evans
Ronald M
RM
Schwabe
John W R
JW
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D009539:Nicotinic Acids / Q000494:pharmacology*; D009930:Organic Chemicals; D011485:Protein Binding; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism
D000924:Anticholesteremic Agents; C423914:LG 268; D008024:Ligands; D009539:Nicotinic Acids; D009930:Organic Chemicals; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C095104:LG 100268