6S4U

LXRbeta ligand binding domain in comlpex with small molecule inhibitors

Summary for 6S4U

• Entry DOI: 10.2210/pdb6s4u/pdb
• Descriptor: Oxysterols receptor LXR-beta, 6-[4-[[3-oxidanyl-1,1-bis(oxidanylidene)-5-phenyl-2-propan-2-yl-3~{H}-1,2-thiazol-4-yl]amino]butyl]pyridine-2-sulfonamide (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: 3
• Total formula weight: 86256.25

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

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: 31799433
DOI: 10.1038/s42003-019-0675-0

Experimental method

X-RAY DIFFRACTION (2.81 Å)