Abstract
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.
Highlights
Ligands that target retinoid-X receptors (RXRs) are emerging as potentially powerful therapies for cancer, diabetes, and the lowering of circulatory cholesterol
Together these findings suggest that RXR ligands may be inefficient at repositioning helix H12
It has emerged that RXR-specific agonists such as Targretin and LG268 may serve as beneficial therapies for the treatment of cancer, diabetes, and other metabolic disorders (13–15)
Summary
Rmerge ϭ ⌺͉I ϪI͘/⌺͗I; Rcryst and Rfree ϭ ⌺͉Fobs Ϫ Fcalc/⌺Fobs. X-ray source/wavelength Resolution (outer shell) Total/unique reflections Redundancy/completeness Rmerge (outer shell) I/ (outer shell) Space group. Rcryst/Rfree (10%) RMSD bonds/angles Average B-factor Ramachandran Favored/additional/generous. ESRF ID14–2/0.933Å 38–2.7 (2.87–2.7) Å 87647/29713 2.9/97.8% 9.8% (26.4%) 5.1 (2.1) C2, a ϭ 123.89, b ϭ 106.88, c ϭ 100.59,  ϭ 122.56 27.7/30.1% 0.009Å/1.4° 51.0 Å3. Displace co-repressor and suggesting that co-activator helps to stabilize the helix in the active conformation
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