6s4u
From Proteopedia
LXRbeta ligand binding domain in comlpex with small molecule inhibitors
Structural highlights
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 PubMedLiver X receptors (LXRs) are attractive drug targets for cardiovascular disease treatment due to their role in regulating cholesterol homeostasis and immunity. The anti-atherogenic properties of LXRs have prompted development of synthetic ligands, but these cause major adverse effects-such as increased lipogenesis-which are challenging to dissect from their beneficial activities. Here we show that LXR compounds displaying diverse functional responses in animal models induce distinct receptor conformations. Combination of hydrogen/deuterium exchange mass spectrometry and multivariate analysis allowed identification of LXR regions differentially correlating with anti-atherogenic and lipogenic activities of ligands. We show that lipogenic compounds stabilize active states of LXRalpha and LXRbeta while the anti-atherogenic expression of the cholesterol transporter ABCA1 is associated with the ligand-induced stabilization of LXRalpha helix 3. Our data indicates that avoiding ligand interaction with the activation helix 12 while engaging helix 3 may provide directions for development of ligands with improved therapeutic profiles. Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands.,Belorusova AY, Evertsson E, Hovdal D, Sandmark J, Bratt E, Maxvall I, Schulman IG, Akerblad P, Lindstedt EL Commun Biol. 2019 Nov 22;2:431. doi: 10.1038/s42003-019-0675-0. eCollection 2019. PMID:31799433[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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