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1.
Biochim Biophys Acta Biomembr ; 1863(9): 183557, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33444621

RESUMO

G protein-coupled receptors (GPCRs) are known to be modulated by membrane cholesterol levels, but whether or not the effects are caused by specific receptor-cholesterol interactions or cholesterol's general effects on the membrane is not well-understood. We performed coarse-grained molecular dynamics (CGMD) simulations coupled with structural bioinformatics approaches on the ß2-adrenergic receptor (ß2AR) and the cholecystokinin (CCK) receptor subfamily. The ß2AR has been shown to be sensitive to membrane cholesterol and cholesterol molecules have been clearly resolved in numerous ß2AR crystal structures. The two CCK receptors are highly homologous and preserve similar cholesterol recognition motifs but despite their homology, CCK1R shows functional sensitivity to membrane cholesterol while CCK2R does not. Our results offer new insights into how cholesterol modulates GPCR function by showing cholesterol interactions with ß2AR that agree with previously published data; additionally, we observe differential and specific cholesterol binding in the CCK receptor subfamily while revealing a previously unreported Cholesterol Recognition Amino-acid Consensus (CRAC) sequence that is also conserved across 38% of class A GPCRs. A thermal denaturation assay (LCP-Tm) shows that mutation of a conserved CRAC sequence on TM7 of the ß2AR affects cholesterol stabilization of the receptor in a lipid bilayer. The results of this study provide a better understanding of receptor-cholesterol interactions that can contribute to novel and improved therapeutics for a variety of diseases.


Assuntos
Colesterol/química , Receptores Acoplados a Proteínas G/química , Modelos Moleculares
2.
Trends Pharmacol Sci ; 37(12): 1055-1069, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27726881

RESUMO

G protein-coupled receptors (GPCRs) constitute the largest class of drug targets in the human genome, which highlights the importance of understanding the molecular basis of their activation, downstream signaling, and regulation. Since 2007, great progress has been made in the field of GPCR structure determination and their signaling complexes at the molecular level. Here, we summarize the high-resolution structures of over 30 different GPCRs with their co-crystallized ligands, and outline the successful strategies involved, including construct design, expression systems, and lipidic cubic phase (LCP) composition, and the many key technical parameters of the crystallization methods. By comparing the success rates of different strategies used in the past, we wish to pave the road for more successful structure-function research for GPCRs in the future.


Assuntos
Lipídeos/química , Receptores Acoplados a Proteínas G/química , Transdução de Sinais/fisiologia , Animais , Cristalização , Genoma Humano , Humanos , Ligantes , Conformação Proteica , Engenharia de Proteínas/métodos , Receptores Acoplados a Proteínas G/metabolismo
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