6k9m

Human LXR-beta in complex with an agonist

spinqualitylabelsall models 6k9m, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6k9m is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: D43 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NR1H2_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 PubMed Based on the co-crystal structures of LXRbeta and its agonists (spiro [pyrrolidine-3,3'-oxindole] derivatives) discovered by us previously, we designed and synthesized a compound library to explore the agonistic activities. The library was screened with luciferase reporter assays, interestingly, it resulted in the discovery of 10 LXR inverse agonists besides 5 LXR agonists. To clarify the mechanism of the actions, we conducted molecular dynamics (MD) simulations on the LXR and inverse agonists complexes, and revealed that H3, H11 and H12 configurations are the key to turn on agonism or inverse agonism status for LXR. Binding tightly with H3, pushing H11 out and destabilizing H12 could form a bigger hydrophobic groove to accommodate NCOR1 to turn on LXR inverse agonism. The inverse agonist 10rr was further studied, and found as a lipogenesis inhibitor through down-regulating LXR target genes SREBP-1c, ACC, FAS and SCD-1, and demonstrated lipid-lowering effects in 3T3-L1 cells, HepG2 cells and mice with Triton WR-1339-induced hyperlipidemia. Therefore, we have proved that LXR inverse agonists can be promising agents for hyperlipidemia treatment. Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors.,Chen Z, Chen H, Zhang Z, Ding P, Yan X, Li Y, Zhang S, Gu Q, Zhou H, Xu J Eur J Med Chem. 2020 Sep 6;206:112793. doi: 10.1016/j.ejmech.2020.112793. PMID:32961480 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Liver X receptor

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