6jio
Human LXR-beta in complex with a ligand
Structural highlights
FunctionNR1H2_HUMAN Orphan receptor. Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (By similarity). Publication Abstract from PubMedThe liver X receptors (LXRs) of the nuclear receptor family are promising therapeutic targets of multiple diseases like lipid disorders, chronic inflammation, as well as different human cancers. To date, no LXR agonists or antagonists can be used in clinics, emphasizing the importance for discovering new LXR modulators. Fragment-based lead discovery (FBLD) is powerful for designing new scaffolds and new mechanistic drugs, but fragment screening has not been applied to LXRs yet, which might be due to the lack of a specific fragment screening method against the dynamic and hydrophobic ligand binding domain (LBD) of LXRs. Herein, a series of fluorescent tracers were designed, synthesized and tested. The tracer based on hyodeoxycholic acid exhibited a good capability for competitively detecting the ligand binding of LXRbeta using a fluorescence polarization approach. Then, 1074 fragments were screened against the LBD of LXRbeta (LXRbeta-LBD), resulting in 27 binding hits. These fragment hits were further tested using the co-activator recruitment assay and reporter gene assay, and efforts in X-ray crystallography fortunately solved a co-crystal structure of LXRbeta-LBD with the fragment F3 (tert-butyl-7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate). The fluorescence-based fragment screening tool and the newly identified LXRbeta binding fragments provide the basis for developing novel LXRbeta modulators. Identify liver X receptor beta modulator building blocks by developing a fluorescence polarization-based competition assay.,Zhang Z, Chen H, Chen Z, Ding P, Ju Y, Gu Q, Xu J, Zhou H Eur J Med Chem. 2019 Sep 15;178:458-467. doi: 10.1016/j.ejmech.2019.06.011. Epub , 2019 Jun 10. PMID:31202993[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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