Abstract
SR141716A binds selectively to the brain cannabinoid (CB1) receptor and exhibits a potent inverse agonist/antagonist activity. Although SR141716A, also known as rimonabant, has been withdrawn from the market due to severe side effects, there remains interest in some of its many potential medical applications. Consequently, it is imperative to understand the mechanism by which SR141716A exerts its inverse agonist activity. As a result of using an approach combining mutagenesis and molecular dynamics simulations, we determined the binding mode of SR141716A. We found from the simulation of the CB1-SR141716A complex that SR141716A projects toward TM5 to interact tightly with the major binding pocket, replacing the coordinated water molecules, and secures the Trp-356(6.48) rotameric switch in the inactive state to promote the formation of an extensive water-mediated H-bonding network to the highly conserved SLAXAD and NPXXY motifs in TM2/TM7. We identify for the first time the involvement of the minor binding pocket formed by TM2/TM3/TM7 for SR141716A binding, which complements the major binding pocket formed by TM3/TM5/TM6. Simulation of the F174(2.61)A mutant CB1-SR141716A complex demonstrates the perturbation of TM2 that attenuates SR141716A binding indirectly. These results suggest SR141716A exerts inverse agonist activity through the stabilization of both TM2 and TM5, securing the Trp-356(6.48) rotameric switch and restraining it from activation.
Highlights
SR141716A binds the cannabinoid receptor 1 (CB1) receptor selectively and exerts inverse agonist activity
In CB1SR141716A_b, the ligand solely occupied the major binding pocket, and both the N1- and the C5-aromatic rings were deeply engaged in the bottom of the major binding pocket, whereas the C3-piperidinyl rings closely interacted with the top of the major binding pocket
C5-aromatic Ring of SR141716A Stabilizes TM5 through Aromatic Stacking—The findings that the Y2755.39A mutation abolished receptor expression (16) and that W2795.43A mutation resulted in lower receptor expression levels than in the wild type (15) suggested that TM5 was important for receptor stabilization
Summary
SR141716A binds the CB1 receptor selectively and exerts inverse agonist activity. Results: We identify a key role of the minor binding pocket for SR141716A binding. The simulation of the CB1-SR141716A complex revealed that SR141716A projects toward TM5 to interact tightly with the major binding pocket, replacing the coordinated water molecules, and secures the Trp-3566.48 rotameric switch in the inactive state to promote the formation of an extensive watermediated H-bonding network to the highly conserved SLAXAD and NPXXY motifs in TM2/TM7. These results suggest SR141716A exerts inverse agonist activity through the stabilization of both TM2 and TM5, securing the Trp-3566.48 rotameric switch and restraining it from activation
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