Table 1. EC 50, ΔΔG, efficacy for... | Rockefeller University Press

Table 1.

EC_50, ΔΔG, efficacy for GLPG1837, and relaxation time constants for the addition and removal of VX-770 for mutations in the five predicted binding sites

	EC₅₀ (μM)	ΔΔG (kJ/mol)	Efficacy (% increase)	τ_{on (VX-770)} (s)	τ_{off (VX-770)} (s)
WT	0.26 ± 0.04	–	115 ± 7	6.7 ± 1.2	361 ± 39
G551D	2.19 ± 0.33	–	4,115 ± 714	5.9 ± 2.4	68 ± 14
Site I
D924A	>3	<−6.06	–	–	–
D924E	0.71 ± 0.07	−2.49	194 ± 8	–	–
D924N	2.29 ± 0.78	−5.39	464 ± 73	78 ± 18	115 ± 7
N1138F/G551D	0.16 ± 0.05	6.48	666 ± 131	–	–
N1138L/G551D	0.08 ± 0.02	8.20	253 ± 32	18 ± 5	268 ± 25
N1138Y/G551D	0.40 ± 0.10	4.21	1,106 ± 279	–	–
S1141K/G551D	0.26 ± 0.02	5.28	1,326 ± 161	14 ± 6	221 ± 50
S1141R/G551D	0.51 ± 0.13	3.61	2,868 ± 479	–	–
S1141T/G551D	1.74 ± 0.31	0.57	2,167 ± 329	–	–
Site II_N
F229A	0.46 ± 0.07	−1.41	135 ± 26	6.2 ± 1.3	338 ± 49
F236A	0.34 ± 0.14	-0.67	81 ± 14	19 ± 8	173 ± 45
Y304A	>3	<−6.06	>80 ± 9	49 ± 11	18 ± 6
Y304F	2.28 ± 0.34	−5.38	82 ± 12	–	–
Y304T	>3	<−6.06	>101 ± 7	–	–
F312A (2 mM ATP)	0.40 ± 0.13	−1.07	26 ± 2	–	–
F312A (30 µM ATP)	1.30 ± 0.26	−3.99	105 ± 12	15 ± 1	38 ± 5
F931A	1.14 ± 0.26	−3.57	83 ± 12	–	–
Site II				–	–
K190A	0.08 ± 0.01	2.92	61 ± 12	–	–
T360A	0.12 ± 0.01	1.92	120 ± 38	–	–
S364A	0.18 ± 0.01	−0.91	126 ± 5	–	–
Site III				–	–
Q237A	0.92 ± 0.32	−3.13	615 ± 101	–	–
D993A	0.36 ± 0.04	−0.81	283 ± 47	–	–
S1149A	0.16 ± 0.03	1.20	139 ± 36	–	–
Site IV
S182A	0.22 ± 0.04	0.41	138 ± 23	8.2 ± 1.5	343 ± 96
S263A	0.27 ± 0.05	−0.09	148 ± 18	6.1 ± 1.5	288 ± 68

	EC₅₀ (μM)	ΔΔG (kJ/mol)	Efficacy (% increase)	τ_{on (VX-770)} (s)	τ_{off (VX-770)} (s)
WT	0.26 ± 0.04	–	115 ± 7	6.7 ± 1.2	361 ± 39
G551D	2.19 ± 0.33	–	4,115 ± 714	5.9 ± 2.4	68 ± 14
Site I
D924A	>3	<−6.06	–	–	–
D924E	0.71 ± 0.07	−2.49	194 ± 8	–	–
D924N	2.29 ± 0.78	−5.39	464 ± 73	78 ± 18	115 ± 7
N1138F/G551D	0.16 ± 0.05	6.48	666 ± 131	–	–
N1138L/G551D	0.08 ± 0.02	8.20	253 ± 32	18 ± 5	268 ± 25
N1138Y/G551D	0.40 ± 0.10	4.21	1,106 ± 279	–	–
S1141K/G551D	0.26 ± 0.02	5.28	1,326 ± 161	14 ± 6	221 ± 50
S1141R/G551D	0.51 ± 0.13	3.61	2,868 ± 479	–	–
S1141T/G551D	1.74 ± 0.31	0.57	2,167 ± 329	–	–
Site II_N
F229A	0.46 ± 0.07	−1.41	135 ± 26	6.2 ± 1.3	338 ± 49
F236A	0.34 ± 0.14	-0.67	81 ± 14	19 ± 8	173 ± 45
Y304A	>3	<−6.06	>80 ± 9	49 ± 11	18 ± 6
Y304F	2.28 ± 0.34	−5.38	82 ± 12	–	–
Y304T	>3	<−6.06	>101 ± 7	–	–
F312A (2 mM ATP)	0.40 ± 0.13	−1.07	26 ± 2	–	–
F312A (30 µM ATP)	1.30 ± 0.26	−3.99	105 ± 12	15 ± 1	38 ± 5
F931A	1.14 ± 0.26	−3.57	83 ± 12	–	–
Site II				–	–
K190A	0.08 ± 0.01	2.92	61 ± 12	–	–
T360A	0.12 ± 0.01	1.92	120 ± 38	–	–
S364A	0.18 ± 0.01	−0.91	126 ± 5	–	–
Site III				–	–
Q237A	0.92 ± 0.32	−3.13	615 ± 101	–	–
D993A	0.36 ± 0.04	−0.81	283 ± 47	–	–
S1149A	0.16 ± 0.03	1.20	139 ± 36	–	–
Site IV
S182A	0.22 ± 0.04	0.41	138 ± 23	8.2 ± 1.5	343 ± 96
S263A	0.27 ± 0.05	−0.09	148 ± 18	6.1 ± 1.5	288 ± 68

ΔΔG was calculated from the following equation: ${Δ G}_{(mutant)} - {Δ G}_{(WT)} = ΔΔ G = - RT \ln \frac{{EC}_{50 (mutant)}}{{EC}_{50 (WT)}} .$

EC_50(WT) was replaced with EC_50(G551D) when the mutation was introduced to G551D-CFTR background.

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