G Protein-Coupled Receptors are transmembrane proteins that can interact with G proteins and possess seven sequences with each of them containing 25 to 35
... [Show More] consecutive hydrophobic residues. They are found only in eukaryotes, including yeast,plants, choanoflagellates, and animals. Analysis of the complete human genome
reveals that there are approximately 800 genes encoding GPCRs. Among them,
approximately 400 are nonolfactory GPCRs. With the exception of slightly over
100 orphan GPCRs for which the ligands are unidentified, the ligands for most of
the nonolfactory GPCRs are known. GPCRs are the receptors for hormones, growth
factors, and other endogenous ligands. They are involved in a wide variety of physiological processes such as the visual sensing, smell sensing, behavioral and mood regulation, regulation of immune system activity and inflammation, autonomic nervous system transmission, and cell density sensing. A diversity of molecules, including ions, small volatile organic odorants, biogenic amines, amino acids, lipids,nucleotides, peptides, and proteins are found to be ligands of GPCRs. Several ligands for GPCR are top selling drugs. Malfunction of GPCR signaling pathways are involved in many diseases, such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer. It is estimated that more than half of the modern drugs’ cellular targets are GPCRs. This makes GPCRs one of the most pursued targets in drug discovery and in assay development.
GPCRs are integral membrane proteins that possess seven transmembrane
helices (Fig. 10.1). The structure of human GPCRs was not resolved until 2007.
However, the 7-helix structural model for GPCRs was proposed long ago based on
a variety of biophysical and biological measurements. The seven transmembrane
helices are numbered from helix 1 to helix 7 starting from the N-terminus to the
C-terminus. The N-terminus resides on the extracellular side of the membrane, and
C-terminus resides on the cytoplasmic side of the membrane. The seven helices are
linked by three extracellular loops and three intracellular loops. The extracellular
loops contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. The extracellular parts of the receptor can also be glycosylated. The structure of bacteriorhodopsin, which is weakly analogous to mammalian GPCRs, was determined by both electron diffraction (1996) and X-ray crystallography (1997). The first crystal structure of a mammalian GPCR, bovine [Show Less]