ABCB1 p.Tyr953Ala
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PMID: 10585407
[PubMed]
Loo TW et al: "Identification of residues in the drug-binding domain of human P-glycoprotein. Analysis of transmembrane segment 11 by cysteine-scanning mutagenesis and inhibition by dibromobimane."
No.
Sentence
Comment
76
The lowest activity was observed in mutant G939V (62% of wild-type activity), while mutant Y953A had the highest (205%) activity.
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ABCB1 p.Tyr953Ala 10585407:76:91
status: NEW79 Wild-type P-gp had an apparent affinity of 24 M verapamil, while mutants F942A, T945A, Q946A, A947L, and Y953A had decreased apparent affinities of 93, 100, 165, 156, and 110 M, respectively.
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ABCB1 p.Tyr953Ala 10585407:79:113
status: NEW84 Moderate decreases in activity (40-50%) were observed for mutants G939V, Q946A, A947L, Y953A, and F957A.
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ABCB1 p.Tyr953Ala 10585407:84:87
status: NEW99 Its maximal colchicine-stimulated ATPase activity was 220% of that of wild-type P-gp, while those of mutants G939V, C956A, and Y953A were moderately increased (165, 145, and 131%, respectively).
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ABCB1 p.Tyr953Ala 10585407:99:127
status: NEW128 TABLE I Drug-stimulated ATPase activity Mutant Drug Verapamil Vinblastine Colchicine Vmax Km Vmax Km Vmax Km % of WTa M % of WT M % of WT mM WT 100 24 100 5.4 100 0.62 I937S 94 22 93 6.1 100 0.69 F938A 106 32 96 5.1 96 0.68 G939V 62 8 45 4.0 165 0.26 I940S 93 32 93 5.6 93 0.65 T941A 100 25 104 5.5 100 0.66 F942A 88 93 30 5.1 24 0.80 S943A 92 26 100 5.2 85 0.62 F944A 93 14 105 5.3 101 0.64 T945A 140 100 165 8.3 56 0.65 Q946A 101 165 57 8.5 18 0.64 A947L 105 156 60 13.0 51 1.87 M948A 103 23 101 5.9 103 0.62 M949A 82 40 96 5.5 61 0.60 Y950A 109 37 119 5.1 99 0.62 F951A 94 31 99 5.2 101 0.64 S952A 108 36 123 5.1 91 0.69 Y953A 205 110 59 8.5 131 0.67 A954L 108 44 13 NDb 8 ND G955V 143 10 104 3.5 220 0.47 C956A 97 24 95 5.3 145 0.63 F957A 126 21 47 4.8 32 1.0 a WT, wild type. b ND, not determined due to low activity.
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ABCB1 p.Tyr953Ala 10585407:128:640
status: NEW147 DISCUSSION Mutants G939V, F942A, T945A, Q946A, A947L, and Y953A in TM11 had altered apparent affinities for verapamil, vinblastine, or colchicine.
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ABCB1 p.Tyr953Ala 10585407:147:58
status: NEW
PMID: 18596043
[PubMed]
Loo TW et al: "Arginines in the first transmembrane segment promote maturation of a P-glycoprotein processing mutant by hydrogen bond interactions with tyrosines in transmembrane segment 11."
No.
Sentence
Comment
7
Mutations that removed hydrogen bond acceptors (Y950F/Y950A or Y953F/Y953A) in TM11 predicted to lie close to Arg-65 or Arg-68 inhibited maturation but did not affect maturation of the G251V parent.
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ABCB1 p.Tyr953Ala 18596043:7:69
status: NEW214 To test if Tyr-950 or Tyr-953 influences the ability of the M68R mutation to promote maturation of the G251V mutant, we introduced the Y950A or Y953A mutations into mutant M68R/ G251V mutant.
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ABCB1 p.Tyr953Ala 18596043:214:144
status: NEW217 The presence of the Y950A or Y953A mutation reduced the maturation efficiency to less than 50% (Fig. 8A, lanes 6 and 9).
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ABCB1 p.Tyr953Ala 18596043:217:29
status: NEW220 Because the L65R mutation also promoted maturation of mutant G251V, we tested whether the Y950A or Y953A mutations would have any effect on maturation of the L65R/G251V mutant.
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ABCB1 p.Tyr953Ala 18596043:220:99
status: NEW221 Fig. 8B shows that introduction of the Y950A mutation caused a relatively large reduction in the maturation efficiency of the mutant (Fig. 8B, lane 3), whereas the Y953A mutation had little effect (Fig. 8B, lane 4).
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ABCB1 p.Tyr953Ala 18596043:221:164
status: NEW222 In contrast, both Y950A and Y953A affected the maturation efficiency of the M68R/G251V mutant.
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ABCB1 p.Tyr953Ala 18596043:222:28
status: NEW223 The Y950A and Y953A mutations did not affect maturation of the (G251V) parent (Fig. 8A, lanes 13 and 14) or wild-type P-gp (data not shown).
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ABCB1 p.Tyr953Ala 18596043:223:14
status: NEW229 Mutants L65R/G251V/Y950F, M68R/G251V/ Y950A/Y953A, and M68R/G251V/Y950F/Y953F were constructed, and the cDNAs were expressed in HEK 293 cells.
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ABCB1 p.Tyr953Ala 18596043:229:44
status: NEW230 Only the Y950F change was introduced into the L65R/G251V mutant since the Y953A change did not affect maturation of the mutant (Fig. 8B, lane 4).
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ABCB1 p.Tyr953Ala 18596043:230:74
status: NEW231 Immunoblot analysis shows the Y950A/Y953A and Y950F/Y953F changes in M68R/G251V (Fig. 8A, lanes 11 and 12) or Y950F change in L65R/G251V (Fig. 8B, lane 5) reduced maturation to levels similar to that observed in the G251V parent.
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ABCB1 p.Tyr953Ala 18596043:231:36
status: NEW
PMID: 24366667
[PubMed]
Donmez Cakil Y et al: "Pore-exposed tyrosine residues of P-glycoprotein are important hydrogen-bonding partners for drugs."
No.
Sentence
Comment
248
Loo and Clarke (2000) demonstrated altered ATPase stimulation of the human protein for the Y953A mutant by verapamil, colchicine, and vinblastine, but did not present evidence for a direct involvement in drug binding.
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ABCB1 p.Tyr953Ala 24366667:248:91
status: NEW