The most frequently encountered class of receptors in the context of hormones is the diverse group of G-protein (for guanine nucleotide binding protein) coupled receptors for which about 800 genes exist in the human genome. Each of these is specific for ligand and response. GPCRs are found in virtually all eukaryotes and participate in many different cellular functions. About half of the GPCR genes encode receptors that have olfactory functions. About 350 GPCRs have hormones, growth factors, and other small molecules as ligands. Figure 1 shows the fundamentals of the structure of these receptors. The receptor itself has seven α-helical membrane spanning regions. This folding generates three extra cellular and three intracellular loops. In some GPCRs palmitoylation of a cysteine residue in the carboxy region results in another loop. The membrane-spanning helices have been shown by X-ray crystallography to cross at angles to one another as depicted on the right side of panel A of Figure 1. The N-terminus of GPCRs is highly variable, as expected from the variety of signals to which these proteins respond. On the right side of panel A are shown three examples of types of ligand binding. Small molecules and small peptides have access to a cleft within the helices for binding, whereas larger proteins, such as the glycoprotein gonadotrophins, bind to a site within a longer, more elaborate N-terminus.
Fig1. G-protein coupled receptors (GPCRs). A. General structure of GPCRs. The G protein-coupled receptors comprise a large family of proteins that share the main structural features shown in the left side of panel A. The predominant characteristic of these proteins is the arrangement of their single polypeptide chains into seven membrane spanning regions, creating three extracellular and three intracellular loops. One or more sites on the intracellular C-terminal portion of the cell may be palmitoylated, which plays a role in the receptor’s position in the membrane. The right-hand side of panel A shows examples of the heterogeneity of the N-terminal portion of GPCRs, reflecting the diversity of ligands for these proteins. Top left: small molecules such as catecholamines or eicosanoids bind to a pocket within the membrane spanning helices; top right, small peptides are partially within a binding pocket but also interact with the extracellular portion of the receptor; bottom, large glycoproteins such as the gonadotrophins or growth factors have binding sites created by the structure of the extracellular portion of the receptor. B. Receptor interaction with G-protein. Inactive G-proteins (left) consist of three subunits in a heterotrimer, α, β, and γ. Two of the subunits, α and γ, have lipid moieties binding them to the membrane and GDP is bound to the α-subunit. When a ligand binds to the receptor and activates it, GDP is replaced with GTP; the α-subunit dissociates from the trimer and moves through the membrane to a nearby protein, an enzyme or ion channel, for example, and activates it, initiating the biological response.
The coupling of a GPCR to a G-protein is illustrated in panel B of Figure 1. G-proteins are composed of three subunits, α, β, and γ—i.e., they are heterotrimeric. The complex is anchored to the membrane by lipid moieties on the α and γ subunits. The contact with the receptor occurs between the cytoplasmic carboxy terminal of the receptor and the α subunit. The α subunit also has a guanine nucleotide binding site. In the absence of ligand activation, GDP occupies this site, and the complex is inactive. When ligand is bound, GTP replaces GDP, Gα dissociates from Gβγ and moves through the membrane to a nearby effector protein, such as an enzyme that produces a second messenger or an ion channel, which itself becomes activated upon binding of the α subunit. Gα has intrinsic GTPase activity, which may be aided by nearby GAP (GTPase acceleratory protein) proteins. Gα–GDP quickly finds and binds to a free Gβγ dimer and the inactive heterotrimer is reformed.
As will be discussed in more detail in section III.A, the biological response that results from a ligand binding to a GPCR depends upon the G-protein attached to the receptor. The human genome encodes about 200 different G-proteins (proteins that bind guanosine nucleotides), a subclass of which are the heterotrimeric proteins (“large G-proteins”) described previously.
