Positive allosteric modulators of lecithin: Cholesterol acyltransferase adjust the orientation of the membrane-binding domain and alter its spatial free energy profile.
PLoS Comput Biol
; 17(3): e1008426, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33720934
ABSTRACT
Lecithincholesterol acyltransferase protein (LCAT) promotes the esterification reaction between cholesterol and phospholipid-derived acyl chains. Positive allosteric modulators have been developed to treat LCAT deficiencies and, plausibly, also cardiovascular diseases in the future. The mechanism of action of these compounds is poorly understood. Here computational docking and atomistic molecular dynamics simulations were utilized to study the interactions between LCAT and the activating compounds. Results indicate that all drugs bind to the allosteric binding pocket in the membrane-binding domain in a similar fashion. The presence of the compounds in the allosteric site results in a distinct spatial orientation and sampling of the membrane-binding domain (MBD). The MBD's different spatial arrangement plausibly affects the lid's movement from closed to open state and vice versa, as suggested by steered molecular dynamics simulations.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Lecitinas
/
Fosfatidilcolina-Esterol O-Aciltransferase
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article