TY - JOUR
T1 - The structural basis for the specificity of retinoid-X receptor-selective agonists
T2 - New insights into the role of helix H12
AU - Love, James D.
AU - Gooch, John T.
AU - Benko, Szilvia
AU - Li, Chuan
AU - Nagy, Laszlo
AU - Krishna K Chatterjee, V.
AU - Evans, Ronald M.
AU - Schwabe, John W.R.
PY - 2002/3/29
Y1 - 2002/3/29
N2 - 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 hRXRβ 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.
AB - 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 hRXRβ 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.
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U2 - 10.1074/jbc.M110869200
DO - 10.1074/jbc.M110869200
M3 - Article
C2 - 11782480
AN - SCOPUS:0037192817
SN - 0021-9258
VL - 277
SP - 11385
EP - 11391
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 13
ER -