01993nas a2200169   4500008004100000022001400041245013300055210006900188260000900257300001600266490000800282520133400290100001901624700002801643700002001671856013201691       2023                        eng d  a1520-610600aPalmitoylation of the glucagon-like peptide-1 receptor modulates cholesterol interactions at the receptor-lipid microenvironment0 aPalmitoylation of the glucagonlike peptide1 receptor modulates c  cDEC   a11000-110100 v1273 a<p>
	The G protein-coupled receptor (GPCR) superfamily of cell surface receptors has been shown to be functionally modulated by post-translational modifications. The glucagon-like peptide receptor-1 (GLP-1R), which is a drug target in diabetes and obesity, undergoes agonist-dependent palmitoyl tail conjugation. The palmitoylation in the C-terminal domain of GLP-1R has been suggested to modulate the receptor-lipid microenvironment. In this work, we have performed coarse-grain molecular dynamics simulations of palmitoylated and nonpalmitoylated GLP-1R to analyze the differential receptor-lipid interactions. Interestingly, the placement and dynamics of the C-terminal domain of GLP-1R are found to be directly dependent on the palmitoyl tail. We observe that both cholesterol and phospholipids interact with the receptor but display differential interactions in the presence and absence of the palmitoyl tail. We characterize important cholesterol-binding sites and validate sites that have been previously reported in experimentally resolved structures of the receptor. We show that the receptor acts like a conduit for cholesterol flip-flop by stabilizing cholesterol in the membrane core. Taken together, our work represents an important step in understanding the molecular effects of lipid modifications in GPCRs.</p>
1 aNaglekar, Amit1 aChattopadhyay, Amitabha1 aSengupta, Durba  uhttps://library.ncl.res.in/content/palmitoylation-glucagon-peptide-1-receptor-modulates-cholesterol-interactions-receptor-lipid02081nas a2200241   4500008004100000022001400041245008800055210006900143260000800212300001100220490000800231520127200239653002801511653002101539653002501560653003501585653002701620100002001647700001901667700002001686700002801706856010501734       2024                        eng d  a0301-462200aProbing the energy landscape of the lipid interactions of the serotonin 1A receptor0 aProbing the energy landscape of the lipid interactions of the se  cOCT  a1072890 v3133 a<p>
	G protein-coupled receptors (GPCRs) are lipid-regulated transmembrane proteins that play a central role in cell signaling and pharmacology. Although the role of membrane lipids in GPCR function is well established, the underlying GPCR-lipid interactions have not been thermodynamically characterized due to the complexity of these interactions. In this work, we estimate the energetics and dynamics of lipid association from coarse-grain simulations of the serotonin1A receptor embedded in a complex membrane. We show that lipids bind to the receptor with varying energetics of 1-4 kT, and timescales of 1-10 mu s. The most favorable energetics and longest residence times are observed for cholesterol, glycosphingolipid GM1, phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Multi-exponential fitting of the contact probability suggests distinct dynamic regimes, corresponding to ps, ns and mu s timescales, that we correlate with the annular, intermediate and nonannular lipid sites. The timescales of lipid binding correspond to high barrier heights, despite their relatively weaker energetics. Our results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.</p>
10aGPCR-lipid interactions10aLipid energetics10aLipid residence time10aMolecular dynamics simulations10aSerotonin 1 a receptor1 aMohole, Madhura1 aNaglekar, Amit1 aSengupta, Durba1 aChattopadhyay, Amitabha  uhttps://library.ncl.res.in/content/probing-energy-landscape-lipid-interactions-serotonin-1a-receptor02953nas a2200169   4500008004100000022001400041245011400055210006900169260000900238300001200247490000800259520231900267100001902586700002802605700002002633856013002653       2026                        eng d  a0006-349500aIncreased cholesterol interactions in the active conformational state of the glucagon-like peptide-1 receptor0 aIncreased cholesterol interactions in the active conformational   cJAN   a546-5560 v1253 a<p>
	The glucagon-like peptide-1 receptor (GLP-1R) is a class B G-protein-coupled receptor that plays an important role in metabolic regulation and consequently is a target for type 2 diabetes and obesity therapeutics. Although cholesterol has been reported to be implicated in receptor activation, its interactions with the receptor during the activation cycle have not been probed. Using coarse-grained molecular dynamics simulations, we have characterized the cholesterol interactions with GLP-1R in four conformational states: the inactive, partially active, GLP-1-bound active, and exenatide-bound active conformational states. We observed that the cholesterol hotspots vary between the receptor states with an increased enrichment of cholesterol around the receptor in the active conformational states. Importantly, more favorable interaction energetics and increased residence times of cholesterol were identified in the active conformational state of the receptor, although lower in magnitude than previously reported. Notably, subtle differences could be distinguished between the GLP-1-bound and exenatide-bound receptor, underlining the ligand-specific effects. Our findings emphasize the increased selectivity of cholesterol toward the active state of GLP-1R and highlight the role of conformational dynamics in receptor-lipid interplay. Our work helps to understand how cholesterol modulates GLP-1R, with potential effects on its role as a regulator in lipid metabolism, thereby opening avenues to leverage these lipid interactions in targeted drug therapy. SIGNIFICANCE This study provides an understanding of how cholesterol directly influences the function of GLP-1R, a key therapeutic target for metabolic diseases including type 2 diabetes and obesity. Using coarse-grained molecular dynamics simulations, we show that cholesterol binding, favorable interactions, and residence times increase when GLP-1R is in its active states. These interactions vary subtly depending on the activating ligand, highlighting ligand-specific effects. Our findings highlight the critical role of conformational dynamics in receptor-lipid interplay and suggest that understanding these cholesterol-GLP-1R interactions could pave the way for novel strategies in targeted drug therapy for metabolic disorders.</p>
1 aNaglekar, Amit1 aChattopadhyay, Amitabha1 aSengupta, Durba  uhttps://library.ncl.res.in/content/increased-cholesterol-interactions-active-conformational-state-glucagon-peptide-1-receptor