G-protein coupled receptors are found in eukaryotes, and are encoded by around 1-3% of the genes in the genome. In this essay I will discuss the general structure and model of activation of GPCRs, as well as how this model has been realised, through the study of bacteriorhodopsin, a homology model of GPCRs. There are many examples of GPCRs illustrating how GPCRs can have a wide range of cellular consequences and I will discuss how the activation of rhodopsin, sphingosine-1-phosphate receptors, and beta-adrenergic receptors, can result in these diverse range of consequences.
GPCRs are composed of 7 transmembrane alpha helices, connected by 6 hydrophilic loops. There is a large amount of sequence variation amongst GPCR in cytoplasmic loop 3, …show more content…
First the binding of a ligand to the extracellular face induces a conformational change of the receptor, involving small changes in the TM helices and connecting loops. GPCRs have multiple binding modes for orthosteric and allosteric ligands, and the propensity of many GPCRs to form dimers or higher order oligomers gives further possibilities for allosteric control. Allosteric ligands bind to a topographically distinct site on a receptor to modulate orthosteric ligand affinity or efficacy. The conformational change enables the inactive G protein, associated with the GPCR on the intracellular side, to exchange its bound GDP for GTP, activating it, causing the bound G protein alpha subunit to dissociate. The alpha subunit can then bind to an effector activating a cascade. GTP is then hydrolysed by the intrinsic GTPase activity of the G protein alpha subunit, and the G protein heterotrimer reforms, ready to interact with another GPCR. A lot of what is known about GPCRs has come from the study of bacteriorhodopsin. Whilst bacteriorhodopsin does not activate any G proteins, and is therefore not a GPCR, it is useful through homology modelling and is available from halobacterium in large quantities, enabling easier crystallisation which is typically challenging with membrane proteins such as GPCRs. Bacteriorhodopsin has 7 TM helices like GPCRs, and functions as a light driven pump involved in photoreception. Net proton movement …show more content…
Rhodopsin is a GPCR found in rod cells of the eye. Rhodopsin consists of Opsin and a 11-cis-retinal chromophore. Absorption of a photon results in the isomerisation of the 11-cis-retinal to an all trans retinal, leading to a conformational change of the GPCR and formation of the intermediate metarhodopsin II, the active state which binds with transducin, a G protein. The conformational change causes the opening of a crevice on the cytoplasmic side, which acts as the binding site for transducin. Arg 135 extends into this crevice to interact with transducin, as a result of the breaking of the salt bridge between Glu 246 and Arg 135 present in the ground state. Active rhodopsin stimulates the exchange of GDP for GTP in transducin and transducin heterotrimer dissociation, allowing transducin-GTP to bind cGMP phosphodiesterase, converting cGMP to 5’-GMP. This drop in cGMP levels results in the closure of cGMP gated channels, blocking the re entry of Na+, resulting in hyperpolarization of the cell. This hyperpolarization signals the optic nerve and enables photoreception. The GTPase activity of transducin hydrolyses GTP to GDP, and the transducin heterotrimer reforms. In this process of activation, the all trans retinal transiently activates opsin, with the retinal then hydrolysed and
GPCRs are composed of 7 transmembrane alpha helices, connected by 6 hydrophilic loops. There is a large amount of sequence variation amongst GPCR in cytoplasmic loop 3, …show more content…
First the binding of a ligand to the extracellular face induces a conformational change of the receptor, involving small changes in the TM helices and connecting loops. GPCRs have multiple binding modes for orthosteric and allosteric ligands, and the propensity of many GPCRs to form dimers or higher order oligomers gives further possibilities for allosteric control. Allosteric ligands bind to a topographically distinct site on a receptor to modulate orthosteric ligand affinity or efficacy. The conformational change enables the inactive G protein, associated with the GPCR on the intracellular side, to exchange its bound GDP for GTP, activating it, causing the bound G protein alpha subunit to dissociate. The alpha subunit can then bind to an effector activating a cascade. GTP is then hydrolysed by the intrinsic GTPase activity of the G protein alpha subunit, and the G protein heterotrimer reforms, ready to interact with another GPCR. A lot of what is known about GPCRs has come from the study of bacteriorhodopsin. Whilst bacteriorhodopsin does not activate any G proteins, and is therefore not a GPCR, it is useful through homology modelling and is available from halobacterium in large quantities, enabling easier crystallisation which is typically challenging with membrane proteins such as GPCRs. Bacteriorhodopsin has 7 TM helices like GPCRs, and functions as a light driven pump involved in photoreception. Net proton movement …show more content…
Rhodopsin is a GPCR found in rod cells of the eye. Rhodopsin consists of Opsin and a 11-cis-retinal chromophore. Absorption of a photon results in the isomerisation of the 11-cis-retinal to an all trans retinal, leading to a conformational change of the GPCR and formation of the intermediate metarhodopsin II, the active state which binds with transducin, a G protein. The conformational change causes the opening of a crevice on the cytoplasmic side, which acts as the binding site for transducin. Arg 135 extends into this crevice to interact with transducin, as a result of the breaking of the salt bridge between Glu 246 and Arg 135 present in the ground state. Active rhodopsin stimulates the exchange of GDP for GTP in transducin and transducin heterotrimer dissociation, allowing transducin-GTP to bind cGMP phosphodiesterase, converting cGMP to 5’-GMP. This drop in cGMP levels results in the closure of cGMP gated channels, blocking the re entry of Na+, resulting in hyperpolarization of the cell. This hyperpolarization signals the optic nerve and enables photoreception. The GTPase activity of transducin hydrolyses GTP to GDP, and the transducin heterotrimer reforms. In this process of activation, the all trans retinal transiently activates opsin, with the retinal then hydrolysed and