Abstract
G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. Biochemical and crystallographic methods together with molecular dynamics simulations and other theoretical techniques provided models of the receptor activation based on the action of so-called “molecular switches” buried in the receptor structure. They are changed by agonists but also by inverse agonists evoking an ensemble of activation states leading toward different activation pathways. Switches discovered so far include the ionic lock switch, the 3-7 lock switch, the tyrosine toggle switch linked with the nPxxy motif in TM7, and the transmission switch. The latter one was proposed instead of the tryptophan rotamer toggle switch because no change of the rotamer was observed in structures of activated receptors. The global toggle switch suggested earlier consisting of a vertical rigid motion of TM6, seems also to be implausible based on the recent crystal structures of GPCRs with agonists. Theoretical and experimental methods (crystallography, NMR, specific spectroscopic methods like FRET/BRET but also single-molecule-force-spectroscopy) are currently used to study the effect of ligands on the receptor structure, location of stable structural segments/domains of GPCRs, and to answer the still open question on how ligands are binding: either via ensemble of conformational receptor states or rather via induced fit mechanisms. On the other hand the structural investigations of homo- and heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor activation that could lead to design highly effective and selective allosteric or ago-allosteric drugs.
Highlights
It is estimated that G protein coupled receptors (GPCRs) are targets for about 50% of drugs currently on the market [1], mainly due to their involvement in signaling pathways related to many diseases i.e. mental [2, 3], metabolic [4] including endocrinological disorders [5, 6], immunological [7] including viral infections [8, 9], cardiovascular [7, 10], inflammatory [11], senses disorders [12] and cancer [13]
Following that work as well as mutagenesis studies, which showed the importance of the (d/e)Ry motif [113], the activation mechanism of GPCRs has been described as a cascade of altering molecular switches in conserved microdomains [20, 114]
While it was clear that simulations on isolated helices could not predict the global interaction and changes in GPCRs, the results showed the usefulness of computational methods for studying ionic locks
Summary
It is estimated that GPCRs are targets for about 50% of drugs currently on the market [1], mainly due to their involvement in signaling pathways related to many diseases i.e. mental [2, 3], metabolic [4] including endocrinological disorders [5, 6], immunological [7] including viral infections [8, 9], cardiovascular [7, 10], inflammatory [11], senses disorders [12] and cancer [13]. The crystallization of 2-adrenergic receptor (2AR) with a diffusible ligand brought surprising results because it revealed quite a different shape of the receptor extracellular side than that of rhodopsin This area is important because it is responsible for the ligand binding and is targeted by many drugs. In a very recent review [25] Unal and Karnik tried to generalize the concept of molecular switches and came to the idea of a coordinated domain coupling in GPCRs which could be a consequence of the dynamic nature of these receptors According to this hypothesis when a ligand is bound to a receptor extracellular domain a decrease in the intrinsic disorder of this domain cooperatively changes the conformation of the neighboring receptor domain. Some other original concepts will be emerging based on the still growing number of crystal structures and other data associated with GPCRs and their complexes
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