Mutations to the putative varenicline-binding residues of the binding site’s principal face
Full data, including error estimates, are reported in Supplemental Table 1.
| Varenicline | ||
|---|---|---|
| EC50 | Fold Shift | |
| μM | ||
| Tyr93 (TyrA) | ||
| Tyra | 2.2 | |
| Phe | 130 | 57 |
| 4-F1-Phe | 34 | 15 |
| F2-Phe | >100b | |
| F3-Phe | >100b | |
| 4-Br-Phe | 12 | 5.4 |
| 4-CN-Phe | 33 | 15 |
| 4-MeO-Phe | 2.2 | 1.0 |
| Trp149 (TrpB) | ||
| Trpa | 2.5 | |
| F3-Trp | 4.1 | 1.6 |
| F4-Trp | 9.6 | 3.8 |
| 4-CN-Trp | 2.1 | 1/1.2 |
| Tyr195 (TyrC2) | ||
| Tyra | 2.1 | |
| Phe | 2.3 | 1.1 |
| 3-F1-Phe | 5.1 | 2.4 |
| 4-F1-Phe | 1.5 | 1/1.4 |
| F2-Phe | 16 | 7.7 |
| F3-Phe | 16 | 7.5 |
| 4-Br-Phe | 3.5 | 1.6 |
| 4-CN-Phe | 21 | 9.9 |
| 4-MeO-Phe | 2.4 | 1.1 |
| Ser150 (TrpB+1) | ||
| Thr | 0.81 | 1/2.5 |
| Tah | 2.4 | 3.0 from Thr |
3-F1-Phe, 3-fluoro-phenylalanine; 4-Br-Phe, 4-bromo-phenylalanine; 4-CN-Phe, 4-cyano-phenylalanine; 4-F1-Phe, 4-fluoro-phenylalanine; F2-Phe, 3,5-difluoro-phenylalanine; F3-Trp, 5,6,7-trifluoro-tryptophan; F4-Trp, 4,5,6,7-tetrafluoro-tryptophan; Tah, α-hydroxythreonine.
↵a Expression of the wild-type receptor with the natural amino acid incorporated by nonsense suppression.
↵b Response of naive oocytes to varenicline doses ≥1 mM obscures complete dose-response data.