Progress in elucidating the structural and dynamic character of G Protein-Coupled Receptor oligomers for use in drug discovery

Abstract

G Protein-Coupled Receptors (GPCRs) are the most targeted group of proteins for the development of therapeutic drugs. Until the last decade, structural information about this family of membrane proteins was relatively scarce, and their mechanisms of ligand binding and signal transduction were modeled on the assumption that GPCRs existed and functioned as monomeric entities. New crystal structures of native and engineered GPCRs, together with important biochemical and biophysical data that reveal structural details of the activation mechanism(s) of this receptor family, provide a valuable framework to improve dynamic molecular models of GPCRs with the ultimate goal of elucidating their allostery and functional selectivity. Since the dynamic movements of single GPCR protomers are likely to be affected by the presence of neighboring interacting subunits, oligomeric arrangements should be taken into account to improve the predictive ability of computer-assisted structural models of GPCRs for effective use in drug design.

Fig. (1)

Current statistics on the growth of class A GPCR crystal structures since the first publication of bovine rhodopsin crystal structure in year 2000. Total number of crystal structures per year, yearly growth of crystal structures, total number of different species of known structure, and total number of GPCR subfamilies of known structure are shown in blue, red, purple, and green colors, respectively.

Fig. (2)

Multidimensional scaling analysis in a two-dimensional Euclidean space of structural differences (as measured by backbone RMSD) between the TM regions of pairs of the twenty-two available class A GPCR crystal structures with an intact TM region (PDB codes: 1F88, 1HZX, 1L9H, 1U19, 1GZM, 2J4Y, 2PED, 2G87, 2HPY, 2I35, 2I36, 2I37, 2RH1, 3C9L, 3C9M, 2ZIY, 2Z73, 3D4S, 2VT4, 3CAP, 3DQB, and 3EML). Coordinates 1 and 2 correspond to the new coordinate system of the dataset after reduction to a two-dimensional space. GPCR crystal structures with structurally similar TM regions are represented by points that are at short Euclidean distance, whereas GPCR crystal structures with dissimilar TM regions are represented by points that are far apart. Available crystal structures of bovine rhodopsin/opsin, squid rhodopsin, β1 adrenergic, β2 adrenergic, and A2A adenosine receptors are represented as cyan, orange, red, blue, and grey points, respectively. Chain A of the corresponding PDB files was always used for the structural analysis, with the only exception of β1-adrenergic receptor for which chain B was used.