Comparison of ligand-binding pocket of orexin receptor antagonists with those of bovine rhodopsin, hβ2AR, and hA2A adenosine receptor

The residues located at a distance of 4.5 Å from 11-cis-retinal (inverse agonist) in the 3D structure of rhodopsin (2.8 Å, PDB id code 1F88) (Palczewski et al., 2000; Teller et al., 2001), within 4 Å of the carazolol (partial inverse agonist) in the 2.4-Å resolution crystal structure of human β2-adrenergic receptor (PDB id code 2RH1) (Cherezov et al., 2007; Rosenbaum et al., 2007), and within 5 Å of the ZM241385 (subtype-selective antagonist) in the 3D structure of human A2A adenosine receptor (2.6 Å, PDB id code 3EML) (Jaakola et al., 2008) are shown for comparison with the critical residues in the binding pocket of orexin receptor antagonists. The generic numbering system proposed by Ballesteros and Weinstein (1995) was used to compare residues in the 7TMD of the different GPCRs.

Position in the 7TMDOpsd_bovin 11-cis-retinal2AR CarazololhA2A ZM241385hOX1hOX2
2.67N.A.N.A.WTT111A (↓)
3.32Ala117Asp113Q126A (↓)Q126A (↓)S. E.WT
3.33Thr118Val114Leu85A127T (↓)A127T (↓)WTT135A (↓)
3.36Gly121Val117WTWTWTV138A (↓)
ECL2b (45.51)Asp192WTD203A (↓)WTD211A (↓)
ECL2b (45.54)Tyr191W206A (↓)W206A (↓)W214A (↓)W214A (↓)
5.38Phe203Tyr199Met177Y215A (↓)Y215A (↓)Y223A (↓)Y223A (↓)
5.42Met207Ser203Asn181F219A (↓)F219A (↓)F227A (↓)F227A (↓)
5.47Phe212Phe208WTY224A (↓)Y232A (↓)Y232A (↓)
6.48Trp265Trp286Trp246S.E.Y311A (↓)Y317A (↓)Y317A (↓)
6.51Tyr268Phe289Leu249N.A.N.A.WTI320A (↓)
7.35Met288Tyr308Met270N.A.N.A.F346A (↑)WT
7.39Ala292Asn312Ile274H344A (↓)H344A (↓)H350A (↓)H350A (↓)
7.43Lys296Tyr316S.E.Y348A (↓)WTY354A (↓)
  • N.A., not available (the mutation was not performed); WT, the same potency as wild type; (↓), decrease in both binding affinity and potency compared with WT; S.E., small but statistically significant decrease in binding affinity; (↑), increase in binding affinity.