Comparison of binding affinities for antagonists in wild-type and mutated AT1 receptors
| [Sar1,Leu8]Angiotensin II | Angiotensin II | L-158,809 | L-162,313 | L-162,389 | L-162,782 | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IC50 | n | Fmut | IC50 | n | Fmut | IC50 | n | Fmut | IC50 | n | Fmut | IC50 | n | Fmut | IC50 | n | Fmut | |
| nm | m | nm | nm | nm | nm | |||||||||||||
| Rat AT1 wild-type | 0.34 ± 0.05 | 7 | 0.84 ± 0.10 | 8 | 0.15 ± 0.02 | 6 | 16.7 ± 2.7 | 12 | 7.72 ± 2.29 | 3 | 28.5 ± 2.2 | 3 | ||||||
| Human AT1 wild-type | 0.25 ± 0.04 | 20 | 0.52 ± 0.11 | 19 | 0.06 ± 0.01 | 19 | 16.1 ± 1.7 | 20 | 3.97 ± 0.69 | 16 | 24.6 ± 2.3 | 17 | ||||||
| TM III | ||||||||||||||||||
| A104V human AT1 | 0.88 ± 0.27 | 6 | 3.5 | 1.19 ± 0.48 | 6 | 2.3 | 0.49 ± 0.14 | 5 | 7.8 | 46.5 ± 12.3 | 7 | 2.9 | 104 ± 33 | 6 | 26 | 480 ± 163 | 6 | 20 |
| V108A rat AT1 | 0.35 ± 0.02 | 5 | 1.0 | 1.10 ± 0.16 | 4 | 1.3 | 0.08 ± 0.01 | 3 | 0.5 | 17.7 ± 2.2 | 5 | 1.1 | 3.09 ± 0.47 | 3 | 0.4 | 27.9 ± 1.4 | 3 | 1.0 |
| S109A human AT1 | 0.79 ± 0.27 | 3 | 3.1 | 1.72 ± 0.62 | 3 | 3.3 | 0.08 ± 0.01 | 3 | 1.2 | 12.5 ± 1.8 | 3 | 0.8 | 6.20 ± 2.17 | 3 | 1.6 | 16.0 ± 1.5 | 3 | 0.7 |
| N111A human AT1 | 0.28 ± 0.10 | 4 | 1.1 | 0.25 ± 0.06 | 4 | 0.5 | 1.10 ± 0.22 | 3 | 18 | 15.7 ± 1.7 | 4 | 1.0 | 15.5 ± 1.5 | 5 | 3.9 | 31.8 ± 4.5 | 5 | 1.3 |
| S115A human AT1 | 0.48 ± 0.11 | 3 | 1.9 | 0.18 ± 0.10 | 3 | 0.4 | 0.10 ± 0.03 | 3 | 1.6 | 22.1 ± 5.5 | 4 | 1.4 | 21.4 ± 3.7 | 3 | 5.4 | 34.5 ± 9.2 | 4 | 1.4 |
| TM IV | ||||||||||||||||||
| W153A human AT1 | 0.24 ± 0.09 | 3 | 1.0 | 0.17 ± 0.04 | 3 | 0.3 | 0.04 ± 0.005 | 3 | 0.6 | 11.5 ± 3.9 | 3 | 0.7 | 6.74 ± 1.66 | 3 | 1.7 | 20.2 ± 3.4 | 3 | 0.8 |
| TM VI | ||||||||||||||||||
| W253A human AT1 | 0.36 ± 0.14 | 3 | 1.4 | 1.97 ± 0.71 | 3 | 3.8 | 0.03 ± 0.01 | 3 | 0.6 | 13.9 ± 1.6 | 3 | 0.9 | 2.61 ± 0.79 | 3 | 0.7 | 26.6 ± 1.0 | 3 | 1.1 |
| H256A rat AT1 | 0.77 ± 0.15 | 3 | 2.3 | 3.90 ± 0.75 | 3 | 4.7 | 0.12 ± 0.02 | 3 | 0.8 | 16.4 ± 1.6 | 3 | 1.0 | 4.67 ± 0.10 | 3 | 0.6 | 22.0 ± 2.5 | 3 | 0.8 |
| T260A human AT1 | 0.46 ± 0.26 | 4 | 1.8 | 0.34 ± 0.13 | 3 | 0.7 | 0.09 ± 0.01 | 3 | 1.5 | 15.7 ± 3.6 | 3 | 1.0 | 6.39 ± 1.17 | 3 | 1.6 | 32.4 ± 9.8 | 4 | 1.3 |
| TM VII | ||||||||||||||||||
| M284A human AT1 | 0.34 ± 0.16 | 3 | 1.4 | 3.97 ± 1.34 | 3 | 7.6 | 0.03 ± 0.003 | 3 | 0.5 | 13.6 ± 3.1 | 3 | 0.9 | 0.80 ± 0.07 | 3 | 0.02 | 15.6 ± 2.7 | 3 | 0.6 |
| T287A human AT1 | 0.89 ± 0.26 | 6 | 3.5 | 8.13 ± 4.28 | 4 | 16 | 0.10 ± 0.03 | 4 | 1.6 | 22.5 ± 1.2 | 3 | 1.4 | 31.6 ± 7.3 | 6 | 8.0 | 25.6 ± 4.3 | 6 | 1.0 |
| A291G human AT1 | 0.17 ± 0.05 | 3 | 0.7 | 3.82 ± 1.63 | 3 | 7.3 | 0.16 ± 0.03 | 3 | 2.5 | 19.1 ± 6.1 | 4 | 1.2 | 7.03 ± 2.24 | 3 | 1.8 | 33.0 ± 1.0 | 3 | 1.3 |
| A291S human AT1 | 0.56 ± 0.29 | 4 | 2.2 | 2.56 ± 1.45 | 4 | 4.9 | 0.18 ± 0.10 | 3 | 2.9 | 40.1 ± 6.1 | 4 | 2.5 | 24.6 ± 5.1 | 3 | 6.2 | 51.3 ± 18.8 | 4 | 2.1 |
| N294A human AT1 | 0.25 ± 0.07 | 4 | 1.0 | 0.52 ± 0.05 | 4 | 1.0 | 0.37 ± 0.16 | 4 | 5.9 | 15.2 ± 2.2 | 5 | 0.9 | 34.1 ± 6.1 | 3 | 8.6 | 28.1 ± 1.6 | 3 | 1.1 |
| N295D rat AT1 | 0.36 ± 0.02 | 5 | 1.1 | 0.44 ± 0.11 | 5 | 0.5 | 2.29 ± 0.69 | 3 | 15 | 22.5 ± 1.8 | 6 | 1.3 | 20.9 ± 0.3 | 3 | 2.7 | 36.9 ± 3.7 | 3 | 1.3 |
| N298A rat AT1 | 0.14 ± 0.02 | 3 | 0.6 | 0.49 ± 0.08 | 3 | 0.9 | 0.61 ± 0.26 | 3 | 9.8 | 14.9 ± 2.1 | 3 | 0.9 | 23.5 ± 2.5 | 3 | 5.9 | 26.9 ± 1.8 | 3 | 1.1 |
F mut is calculated as IC50 (mutant receptor)/IC50 (wild-type AT1 receptor). This corresponds to fold decrease in affinity.