ABCMdb

ABCC8 p.Tyr179Phe

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Publications

PMID: 21685390 [PubMed] Marquer C et al: "Structural model of ligand-G protein-coupled receptor (GPCR) complex based on experimental double mutant cycle data: MT7 snake toxin bound to dimeric hM1 muscarinic receptor."

No. Sentence Comment

156 hM1 mutant Region pKi NMS pKX MT7 KX(mut)/KX(WT) WT 10.22 Ϯ 0.04 10.47 Ϯ 0.04 H90A E1 10.20 Ϯ 0.09 10.66 Ϯ 0.20 0.6 W91A E1 9.23 ؎ 0.33 9.30 ؎ 0.06 14.9 W101A TM3 9.29 Ϯ 0.02 9.79 Ϯ 0.13 4.8 Y166A E2 9.83 Ϯ 0.03 10.33 Ϯ 0.32 1.4 L167F E2 9.93 Ϯ 0.02 10.48 Ϯ 0.11 1.0 E170A E2 10.20 Ϯ 0.04 10.20 Ϯ 0.07 1.9 E170K E2 10.16 Ϯ 0.02 9.31 ؎ 0.11 14.6 R171A E2 9.76 Ϯ 0.01 9.50 ؎ 0.29 9.4 L174A E2 10.21 Ϯ 0.08 10.51 Ϯ 0.01 0.9 L174P E2 10.15 Ϯ 0.01 9.37 ؎ 0.14 12.5 Q177E E2 10.08 Ϯ 0.04 10.58 Ϯ 0.17 0.8 Y179F E2 9.85 Ϯ 0.02 9.25 ؎ 0.18 16.5 L183A E2 10.00 Ϯ 0.11 10.44 Ϯ 0.20 1.1 Q185A E2 10.18 Ϯ 0.10 10.59 Ϯ 0.37 0.8 K392A E3 10.20 Ϯ 0.12 10.57 Ϯ 0.18 0.8 D393A E3 9.96 Ϯ 0.09 10.50 Ϯ 0.23 0.9 E397A E3 10.21 Ϯ 0.06 10.54 Ϯ 0.20 0.9 W400A TM7 10.12 Ϯ 0.04 9.43 ؎ 0.02 11.0 E401A TM7 9.76 Ϯ 0.02 10.20 Ϯ 0.10 1.9 TABLE 2 Affinity constants and variations in free energy of interaction of wild-type and modified MT7 toxins for wild-type and mutated hM1 receptors Data were inferred from binding experiments with ͓3 H͔NMS and calculated with the ternary complex equation. Login to comment
160 hM1 receptor hM1 region MT7 toxin MT7 loop pKX ⌬⌬Gint kcal/mol WT WT 10.47 Ϯ 0.04 H90A E1 WT 10.66 Ϯ 0.20 W10A 1 11.62 Ϯ 0.28 -2.08 Ϯ 0.40 Y30A 2 9.55 Ϯ 0.28 ؉1.14 Ϯ 0.37 Y51A 3 10.42 Ϯ 0.13 ϩ0.20 Ϯ 0.11 R52A 3 10.42 Ϯ 0.44 -0.04 Ϯ 0.59 W91A E1 WT 9.30 Ϯ 0.06 W10A 1 7.69 Ϯ 0.05 ؉1.09 Ϯ 0.07 Y30A 2 7.81 Ϯ 0.07 ؉1.64 Ϯ 0.09 Y51A 3 8.79 Ϯ 0.17 ϩ0.44 Ϯ 0.24 R52A 3 8.54 Ϯ 0.13 ϩ0.66 Ϯ 0.17 W101A TM3 WT 9.79 Ϯ 0.13 W10A 1 8.57 Ϯ 0.14 ϩ0.57 Ϯ 0.19 Y30A 2 9.08 Ϯ 0.09 ϩ0.60 Ϯ 0.11 R34A 2 7.74 Ϯ 0.10 -0.37 Ϯ 0.21 R52A 3 9.05 Ϯ 0.19 ϩ0.62 Ϯ 0.25 E170A E2 WT 10.20 Ϯ 0.07 W10A 1 8.42 Ϯ 0.20 ؉1.33 Ϯ 0.25 Y30A 2 8.84 Ϯ 0.28 ؉1.47 Ϯ 0.38 S32A 2 8.63 Ϯ 0.16 ؉1.43 Ϯ 0.22 R34A 2 7.50 Ϯ 0.36 ϩ0.60 Ϯ 0.49 M35A 2 8.63 Ϯ 0.13 ؉0.87 Ϯ 0.17 Y36A 2 7.97 Ϯ 0.13 ؉1.24 Ϯ 0.17 Y51A 3 9.71 Ϯ 0.31 ϩ0.41 Ϯ 0.42 R52A 3 8.57 Ϯ 0.18 ؉1.77 Ϯ 0.27 R171A E2 WT 9.50 Ϯ 0.29 K5A 1 9.25 Ϯ 0.18 -0.10 Ϯ 0.24 W10A 1 7.76 Ϯ 0.18 ؉1.26 Ϯ 0.24 Y30A 2 8.22 Ϯ 0.14 ؉1.49 Ϯ 0.43 S32A 2 8.46 Ϯ 0.08 ؉0.72 Ϯ 0.11 M35A 2 7.68 Ϯ 0.46 ؉1.20 Ϯ 0.62 Y36A 2 7.03 Ϯ 0.21 ؉1.55 Ϯ 0.28 K48A 2 9.48 Ϯ 0.02 -0.13 Ϯ 0.02 Y51A 3 8.67 Ϯ 0.12 ؉0.89 Ϯ 0.16 R52A 3 8.35 Ϯ 0.17 ؉1.17 Ϯ 0.23 L174A E2 WT 10.51 Ϯ 0.01 W10A 1 9.19 Ϯ 0.20 ؉0.71 ؎ 0.27 Y30A 2 9.45 Ϯ 0.17 ؉1.08 Ϯ 0.23 S32A 2 9.66 Ϯ 0.20 ϩ0.48 Ϯ 0.27 R34A 2 7.52 Ϯ 0.13 ؉1.19 Ϯ 0.42 M35A 2 8.72 Ϯ 0.10 ؉1.16 Ϯ 0.13 Y36A 2 8.59 Ϯ 0.23 ؉0.83 Ϯ 0.31 Y51A 3 10.06 Ϯ 0.23 ϩ0.37 Ϯ 0.31 R52A 3 9.23 Ϯ 0.22 ؉1.35 Ϯ 0.29 Y179F E2 WT 9.25 Ϯ 0.18 K5A 1 9.15 Ϯ 0.15 -0.28 Ϯ 0.20 W10A 1 7.62 Ϯ 0.19 ؉1.13 Ϯ 0.25 R34A 2 Ͻ6 > ؉1.35 K48A 2 9.21 Ϯ 0.01 -0.09 Ϯ 0.01 R52A 3 Ͻ6 >؉4.00 K392A E3 WT 10.57 Ϯ 0.18 W10A 1 9.88 Ϯ 0.22 -0.13 Ϯ 0.29 F11A 1 10.19 Ϯ 0.20 ϩ0.27 Ϯ 0.27 D393A E3 WT 10.50 Ϯ 0.23 S8A 1 10.05 Ϯ 0.06 ϩ0.21 Ϯ 0.08 W10A 1 10.10 Ϯ 0.02 -0.53 Ϯ 0.02 F11A 1 10.21 Ϯ 0.24 ϩ0.35 Ϯ 0.09 Y51A 3 10.00 Ϯ 0.34 ϩ0.42 Ϯ 0.46 E397A E3 WT 10.54 Ϯ 0.20 W10A 1 8.64 Ϯ 0.22 ؉1.58 Ϯ 0.31 F11A 1 9.89 Ϯ 0.21 ϩ0.64 Ϯ 0.28 W400A TM7 WT 9.43 Ϯ 0.02 K5A 1 9.60 Ϯ 0.05 -0.66 Ϯ 0.07 W10A 1 7.61 Ϯ 0.32 ؉1.38 Ϯ 0.44 F11A 1 8.29 Ϯ 0.25 ؉1.29 Ϯ 0.33 Y30A 2 8.49 Ϯ 0.08 ؉0.90 Ϯ 0.10 S32A 2 8.64 Ϯ 0.15 ϩ0.38 Ϯ 0.20 R34A 2 Ͻ6 >؉1.58 M35A 2 8.52 Ϯ 0.13 -0.11 Ϯ 0.12 Y36A 2 7.37 Ϯ 0.29 ؉1.00 Ϯ 0.38 K48A 3 9.41 Ϯ 0.06 -0.12 Ϯ 0.07 R52A 3 7.73 Ϯ 0.08 ؉0.91 Ϯ 0.17 E401A TM7 WT 10.20 Ϯ 0.10 R34A 2 7.41 Ϯ 0.37 ϩ0.61 Ϯ 0.45 Modeling of MT7-Dimeric hM1 Muscarinic Receptor Complex 31666 account this flexibility, we generated open conformations of loop E2 by molecular dynamics. Login to comment

PMID: 20660086 [PubMed] Jacobson MA et al: "The M1 muscarinic receptor allosteric agonists AC-42 and 1-[1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one bind to a unique site distinct from the acetylcholine orthosteric site."

No. Sentence Comment

167 In comparison, the affinity of N-desmethylclozapine was only slightly changed on W101A and W101F, where a 2-fold decrease and 1.25-fold increase in potency were measured, respectively. Substitution of Tyr179 with either alanine or phenylalanine resulted in only minor changes in functional potencies -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 Ile Phe Log [Agonist] (M) %Max -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 Asn Gly Log [Agonist] (M) %Max -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 Asn Thr Log [Agonist] (M) %Max Ach AC42 TBPB Fig. 4. Login to comment
173 The affinity of acetylcholine was decreased by only 2.5and 2-fold on Y179A and Y179F, respectively. Login to comment
176 In comparison, AC-42 exhibited a 2.8-fold decrease in affinity on Y179F, whereas the affinity for TBPB was unchanged compared with wild-type M1 receptors. Login to comment