Influence of Cholesterol and Its Stereoisomers on Members of the Serotonin Receptor Family.
J Mol Biol
; 431(8): 1633-1649, 2019 04 05.
Article
en En
| MEDLINE
| ID: mdl-30857969
ABSTRACT
Despite the ubiquity of cholesterol within the cell membrane, the mechanism by which it influences embedded proteins remains elusive. Numerous G-protein coupled receptors exhibit dramatic responses to membrane cholesterol with regard to the ligand-binding affinity and functional properties, including the 5-HT receptor family. Here, we use over 25⯵s of unbiased atomistic molecular dynamics simulations to identify cholesterol interaction sites in the 5-HT1B and 5-HT2B receptors and evaluate their impact on receptor structure. Susceptibility to membrane cholesterol is shown to be subtype dependent and determined by the quality of interactions between the extracellular loops. Charged residues are essential for maintaining the arrangement of the extracellular surface in 5-HT2B; in the absence of such interactions, the extracellular surface of the 5-HT1B is malleable, populating a number of distinct conformations. Elevated cholesterol density near transmembrane helix 4 is considered to be conducive to the conformation of extracellular loop 2. Occupation of this site is also shown to be stereospecific, illustrated by differential behavior of nat-cholesterol isomers, ent- and epi-cholesterol. In simulations containing the endogenous agonist, serotonin, cholesterol binding at transmembrane helix 4 biases bound serotonin molecules toward an unexpected binding mode in the extended binding pocket. The results highlight the capability of membrane cholesterol to influence the mobility of the extracellular surface in the 5-HT1 receptor family and manipulate the architecture of the extracellular ligand-binding pocket.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Colesterol
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Receptor de Serotonina 5-HT1B
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Receptor de Serotonina 5-HT2B
Límite:
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article