02251nas a2200253   4500008004100000022001400041245006200055210006100117260000800178300001100186490000800197520145900205653002701664653001601691653002601707653003201733653001601765653003601781100002101817700002001838700002801858700002001886856009101906       2020                        eng d  a0009-308400aRole of cholesterol-mediated effects in GPCR heterodimers0 aRole of cholesterolmediated effects in GPCR heterodimers  cMAR  a1048520 v2273 a<p>G protein-coupled receptors (GPCRs) are transmembrane receptors that mediate a large number of cellular responses. The organization of GPCRs into dimers and higher-order oligomers is known to allow a larger repertoire of downstream signaling events. In this context, a crosstalk between the adenosine and dopamine receptors has been reported, indicating the presence of heterodimers that are functionally relevant. In this paper, we explored the effect of membrane cholesterol on the adenosine(2A) (A(2A)) and dopamine D-3 (D-3) receptors using coarse-grain molecular dynamics simulations. We analyzed cholesterol interaction sites on the A(2A) receptor and were able to reproduce the sites indicated by crystallography and previous atomistic simulations. We predict novel cholesterol interaction sites on the D-3 receptor that could be important in the reported cholesterol sensitivity in receptor function. Further, we analyzed the formation of heterodimers between the two receptors. Our results suggest that membrane cholesterol modulates the relative population of several co-existing heterodimer conformations. Both direct receptor-cholesterol interaction and indirect membrane effects contribute toward the modulation of heterodimer conformations. These results constitute one of the first examples of modulation of GPCR hetero-dimerization by membrane cholesterol, and could prove to be useful in designing better therapeutic strategies.</p>
10aAdenosine(2A) receptor10aCholesterol10aDopamine D-3 receptor10aG protein-coupled receptors10aHeterodimer10aMARTINI coarse-grain simulation1 aPrasanna, Xavier1 aMohole, Madhura1 aChattopadhyay, Amitabha1 aSengupta, Durba  uhttps://library.ncl.res.in/content/role-cholesterol-mediated-effects-gpcr-heterodimers