Endocrinology 4 - GPCRs & G Proteins G protein-couple receptor (GCPRs) - Largest family of human cell surface receptors - Involved in smell, taste, vision - Bind a huge array of molecules - Characterised by 7 transmembrane domains: o Piece of proteins that spans across the memb . n-terminus on the outside · ligand binding c-terminus on the inside · linked to helices involved in coupling to proteins Extracellular Intracellular - Used in drugs o ~ 50 % of pharmaceuticals target GCPRs o 25% of top selling drugs Nearly all drugs work on transmembrane proteins instead of intracellular - GCPR ligands o Light Taste and smell molecules (~20%) o Pheromones Histamines o Hormones e.g. oxytocin, (love hormone) adrenalin - 5 GCPR distinct families - GRAFS System o Glutamate-like o Rhodopsin-like o Adhesion-like o Frizzled-like o Secretin-like There are two naming systems. Learn both. This is the GRAFS system: Found a GCPR that is architecturally similar and . .. b - Family System o Family A - Rhodopsin · bind small molecules like light o Family B - Secretin . Bind peptide hormones " Have huge extracellular domains with disulphide bonds o Family C - Glutamate " lons and small molecules · Act as dimers - bringing two proteins together . Extracellular domains that form venous fly traps motifs o Adhesion Family " Ligand is mostly unknown . Sticks cells together · Have cleavable extracellular domains . Which can activate or deactivate the ligands o Frizzled Family
Wnt Proteins G Proteins - Guanine nucleotide binding proteins eg. GTP (analogous to ATP) and GDP (analogous to ADP) - GPCRs signal via heterotrimeric G proteins (3 different parts) Alpha - 16 . Alpha subunit binds guanine nucleotides (GD ?) o Beta - 5 o Gamma - 12 y a - G proteins act as molecular switches - Three states; B GDP 00 o Empty o Inactive (bound to GDP) o Active Releases GDP - This GDP is then replaced by GTP producing an active G protein - GCPR sits on the cell membrane and binds to a ligand These conformational changes are really small, small amount of energy An active GCPR - Causes the receptor to call for a G protein - When not bound the GCPR is bound with no gap at the bo - After its bound, it opens up and a G protein can bind - Acyl chains on the G protein hold it close to the GCPR o To keep it close to the GCPR so it's there ready to bin - This causes a conformational change in the alpha subunit L - - Making it bind to GTP - Another conformational change and so it disassociates from the receptor o And the beta-gamma - G-alpha then goes on to activate the signalling cascade G protein (in)activators - G proteins are tuned off by GTPase activity - GTPase break down GTP - To turn them off, the alpha subunit will hydrolyse the GTP back into GDP (takes a long