The Journal of Physical Chemistry B Article g DIR KWVDICSASSSWFFNEVW D2R VEVDVCTVSSSWFFHYTY D3R VEVDVCTVSSSWEFHYTY Binding orientation in DIR Binding orientation in D2R and D3R t characteristics of DiR, D2R, and D3R.(a, b, and c) Binding pocket lining of DiR, D2R, and D3R.(d, e, and ape of DiR, D2R, and d3r (g) Binding pocket residue s ce alignment of DiR, D2R, and D3R.(h) Binding orientations DIR, D2R, and D3R. Residues colored in green are conserved in the binding of L-SPD with DIR, D2R, and D3R; those colored conserved in the binding of l-SPD with D2R and D3R. Residues colored in orange are unique in the binding of l-SPD with DiR. A-OH of I-SPD hydrogen bonded to SS. 42( Figure Sb, c), which bonding is important for 1-SPD to bind with D2R since is generally accepted as a key contributor to antagonist binding structural modification showed that the substitution of A-OH in both dopamine receptors and P2AR 49, 51 52 This hydrogen with a methoxyl group resulted in a ca. 12-fold loss of affinity 8126 dx. dolora/o.021/p30492351 Phys. Chem. B2012116,8121-813A-OH of l-SPD hydrogen bonded to S5.42 (Figure 5b,c), which is generally accepted as a key contributor to antagonist binding in both dopamine receptors and β2AR.49,51,52 This hydrogen bonding is important for l-SPD to bind with D2R since structural modification showed that the substitution of A-OH with a methoxyl group resulted in a ca. 12-fold loss of affinity Figure 5. Binding pocket characteristics of D1R, D2R, and D3R. (a, b, and c) Binding pocket lining of D1R, D2R, and D3R. (d, e, and f) Binding pocket shape of D1R, D2R, and D3R. (g) Binding pocket residue sequence alignment of D1R, D2R, and D3R. (h) Binding orientations of l-SPD in D1R, D2R, and D3R. Residues colored in green are conserved in the binding of l-SPD with D1R, D2R, and D3R; those colored in cyan are conserved in the binding of l-SPD with D2R and D3R. Residues colored in orange are unique in the binding of l-SPD with D1R. The Journal of Physical Chemistry B Article 8126 dx.doi.org/10.1021/jp3049235 | J. Phys. Chem. B 2012, 116, 8121−8130