Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands.
Commun Biol
; 2: 431, 2019.
Article
em En
| MEDLINE
| ID: mdl-31799433
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 LXRß 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Conformação Proteica
/
Modelos Moleculares
/
Receptores X do Fígado
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article