| First Author | Belorusova AY | Year | 2019 |
| Journal | Commun Biol | Volume | 2 |
| Pages | 431 | PubMed ID | 31799433 |
| Mgi Jnum | J:289136 | Mgi Id | MGI:6433198 |
| Doi | 10.1038/s42003-019-0675-0 | Citation | Belorusova AY, et al. (2019) Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands. Commun Biol 2:431 |
| abstractText | Liver 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. |
