Demystifying the three dimensional structure of G protein-coupled receptors (GPCRs) with the aid of molecular modeling

Abstract

We review our recent work on adenosine receptors, a family of GPCRs; focusing our attention on A3 adenosine receptor, we have demonstrated that the reciprocal integration of different theoretical and experimental disciplines can be very useful for the successful protein-based design of new, potent and selective receptor ligands.

Fig. 1

The “world of human GPCRs”. A distribution of the 508 human GPCRs that have been discovered so far, grouped according to the type of natural ligand that binds to them. Orphan receptors are receptors of yet unknown function.

Fig. 2

Signal transduction pathways associate with the activation of the human adenosine receptors.

Fig. 3

Heptahelical diagram of the human A3 adenosine receptor. The putative transmembrane domains were modified according to the high resolution rhodopsin model. Amino acids mutated in the present study are circled. Residues 286–295 correspond to an extra helical domain in rhodopsin, which is discontinuous from TM7.

Fig. 4

A) Stereoview of the complete topology of human A3 receptor obtained by a homology modeling approach. B) Stereoview of the human A₃ receptor transmembrane helical bundle model viewed along the helical axes from the extracellular end (right) and perpendicular to the helical axes (left).

Fig. 5

Chemical structures of the most representative members of the several classes of heterocyclic compounds identified as A₃ adenosine antagonists.

Fig. 6

CoMFA steric and electrostatic contour plots from the analysis based on the A₃ receptor 3D-QSAR without cross-validation. Compound MRS1041 shown inside the field. Favoring activity: green, bulky group (contribution level 80%); yellow, less bulky; blue, positive charge (contribution level 70%); red, negative charge.

Fig. 7

Side view of the human A₃–MRS1476 complex model. The side chains of the important residues in proximity ( < 5 Å) to the docked pyridine molecule are highlighted and labeled: Leu90 (TM3), Phe182 (TM5), Ser242 (TM6), Ser247 (TM6), Asn250 (TM6), Ser271 (TM7), His272 (TM7) and Ser275 (TM7). The steric and the electrostatic contour plots, obtained from the CoMFA analysis, are included into the ligand binding cavity.

Fig. 8

Side view of the human A₃–5 complex model. The side chains of the important residues in proximity to the docked 5 molecule are highlighted and labeled.

Fig. 9

Side view of the human A₃–6 complex model. The side chains of the important residues in proximity to the docked 6 molecule are highlighted and labeled.