6K9M
Human LXR-beta in complex with an agonist
Summary for 6K9M
| Entry DOI | 10.2210/pdb6k9m/pdb |
| Descriptor | Oxysterols receptor LXR-beta, ~{tert}-butyl (2'~{S},3~{S})-2-oxidanylidene-2'-propan-2-yl-spiro[1~{H}-indole-3,3'-pyrrolidine]-1'-carboxylate (3 entities in total) |
| Functional Keywords | nuclear receptor, dna binding protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 126008.04 |
| Authors | |
| Primary citation | Chen, Z.,Chen, H.,Zhang, Z.,Ding, P.,Yan, X.,Li, Y.,Zhang, S.,Gu, Q.,Zhou, H.,Xu, J. Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors. Eur.J.Med.Chem., 206:112793-112793, 2020 Cited by PubMed Abstract: Based on the co-crystal structures of LXRβ 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. PubMed: 32961480DOI: 10.1016/j.ejmech.2020.112793 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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