6S4T
LXRbeta ligand binding domain in comlpex with small molecule inhibitors
Summary for 6S4T
| Entry DOI | 10.2210/pdb6s4t/pdb |
| Descriptor | Oxysterols receptor LXR-beta, 2-[4-[[3-[3-(phenylmethyl)-8-(trifluoromethyl)quinolin-4-yl]phenoxy]methyl]phenyl]ethanoic acid (3 entities in total) |
| Functional Keywords | liver x receptor beta lxrb lxr beta nuclear hormone receptor receptor ligand binding domain, nuclear protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29326.55 |
| Authors | Sandmark, J.,Jansson, A. (deposition date: 2019-06-28, release date: 2019-11-27, Last modification date: 2024-05-15) |
| Primary citation | Belorusova, A.Y.,Evertsson, E.,Hovdal, D.,Sandmark, J.,Bratt, E.,Maxvall, I.,Schulman, I.G.,Akerblad, P.,Lindstedt, E.L. Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands. Commun Biol, 2:431-431, 2019 Cited by PubMed Abstract: 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 LXRα and LXRβ while the anti-atherogenic expression of the cholesterol transporter ABCA1 is associated with the ligand-induced stabilization of LXRα 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. PubMed: 31799433DOI: 10.1038/s42003-019-0675-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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