G protein-coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across cell membranes and represent major targets in the development of novel drug candidates in all clinical areas. Although there have been some recent leads, structural information on GPCRs is relatively rare due to the difficulty associated with crystallization. A specific reason for this is the intrinsic flexibility displayed by GPCRs, which is necessary for their functional diversity. Since GPCRs are integral membrane proteins, interaction of membrane lipids with them constitutes an important area of research in GPCR biology. In particular, membrane cholesterol has been reported to have a modulatory role in the function of a number of GPCRs. The role of membrane cholesterol in GPCR function is discussed with specific example of the receptor. Recent results show that GPCRs are characterized with structural motifs that preferentially associate with cholesterol. An emerging and important concept is oligomerization of GPCRs and its role in GPCR function and signaling. The role of membrane cholesterol in GPCR oligomerization is highlighted. Future research in GPCR biology would offer novel insight in basic biology and provide new avenues for drug discovery. 1. G Protein-Coupled Receptors as Cellular Nanomachines The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals and is involved in information transfer (signal transduction) from outside the cell to the cellular interior [1–4]. GPCRs are typically seven transmembrane domain proteins (see Figure 1) and include > 800 members which are encoded by ~5% of human genes [5]. Evolutionary data reveal that GPCRs and G protein signaling dates back ~1.2 billion years, prior to plants, fungi, and animals emerging from a common ancestor [6]. GPCRs in mammals are classified into five main families, named Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin according to the GRAFS classification [7, 8]. Each of these families is characterized by long evolutionary history. Figure 1: A schematic representation of G protein-coupled receptor (GPCR) and its signaling. GPCRs are integral membrane proteins with seven transmembrane domains. A consequence of having odd number of transmembrane passes is that the amino and carboxy terminals are localized on opposite sides of the cellular membrane. The helices are often tilted resulting in compact structure due to helix-helix interaction and packing. GPCRs are activated by a wide variety of ligands that include
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