Fig. 3.

a, b Molecular model of the human P2Y₁ receptor based on the structure of the β₂-adrenergic receptor. The P2Y₁ receptor is shown in complex with a selective antagonist (MRS2500) (b) and a selective agonist (MRS2365) (a). The residues shown are those that, when mutated, lead to a decrease of potency of 20 times or higher. The helices are color coded as TM1 (red), TM2 (orange), TM3 (yellow), TM4 (light green), TM5 (dark green), TM6 (cyan), and TM7 (purple). c, d Molecular model of the human P2Y₁₂ receptor based on the structure of the A_2A adenosine receptor. The P2Y₁₂ receptor is shown in complex with a nonselective agonist (2-MeSADP) (c) and a selective non-nucleotide antagonist (PSB-0739) (d). The helices are color-coded in a progression from TM1 (red) to TM7 (yellow). Two disulfide bridges and a salt bridge give rigidity to the extracellular domains of the P2Y₁ and P2Y₁₂ receptors. In the antagonist-bound state of the P2Y₁ receptor, a salt-bridge between R128 and D204 provides an additional link between TM3 and EL2. Our models suggest that agonist binding causes a disruption of this additional bridge as well as a counter-clockwise rotation (when observed from the extracellular side) of Lys280(6.55). Molecular modeling of these receptors was reported previously [24, 25, 35, 36, 38, 40, 41, 67, 89, 117]