ABCB1 p.Phe978Ala
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PMID: 10331089
[PubMed]
Ambudkar SV et al: "Biochemical, cellular, and pharmacological aspects of the multidrug transporter."
No.
Sentence
Comment
47
Table 1 List of mutations in human, mouse, and hamster P-glycoproteins that affect substrate specificitya aa mutation Region Sourceb Reference H61R, F, K, M, W, Y TM 1 Human MDR1 149, 150 ABC20c G64R TM 1 Human MDR1 150 L65R TM 1 Human MDR1 150 aa78-97 EC 1 Human MDR1 151 Q128Hd TM 2 Mouse mdr3 152 R138H IC 1 Mouse mdr3 152 Q139H, R IC 1 Mouse mdr3 152 Q141V IC 1 Human MDR1 15319, Q145H IC 1 Mouse mdr3 152 E155G, K IC 1 Mouse mdr3 152 F159I IC 1 Mouse mdr3 152 D174G IC 1 Mouse mdr3 152 S176G, P IC 1 Mouse mdr3 152 K177I IC 1 Mouse mdr3 152 N179S IC 1 Mouse mdr3 152 N183S/G185V IC 1 Human MDR1 154 G183D IC 1 Mouse mdr3 152 G185V IC 1 Human MDR1 155-157 G187V IC 1 Human MDR1 153 A192T TM 3 Mouse mdr3 152 F204S EC 2 Mouse mdr3 152 W208G EC 2 Mouse mdr3 152 K209E EC 2 Mouse mdr3 152 L210I TM 4 Mouse mdr3 152 T211P TM 4 Mouse mdr3 152 I214T TM 4 Mouse mdr3 152 P223A TM 4 Human MDR1 158 G288V IC 2 Human MDR1 153 I299M, T319S, L322I, TM 5, EC3, Human MDR1 159 G324K, S351N IC 3 F335A TM 6 Human MDR1 19 F335 TM 6 Human MDR1 160 V338A TM 6 Human MDR1 161 G338A, A339P TM 6 Hamster PGY1 162, 163 A339P TM 6 Hamster PGY1 163 G341V TM 6 Human MDR1 161 K536R, Q N-NBD Human MDR1 164 ERGA → DKGT N-NBD Mouse mdr3 165 aa 522-525 T578C N-NBD Mouse mdr3 165 (Continued) G830V IC 4 Human MDR1 P866A TM 10 Human MDR1 158 F934A TM 11 Mouse mdr3 166 G935A TM 11 Mouse mdr3 166 I936A TM 11 Mouse mdr3 166 F938A TM 11 Mouse mdr3 166 S939A TM 11 Mouse mdr3 166 S939F TM 11 Mouse mdr3 167, 168 S941F TM 11 Mouse mdr1 167, 168 T941A TM 11 Mouse mdr3 166 Q942A TM 11 Mouse mdr3 166 A943G TM 11 Mouse mdr3 166 Y946A TM 11 Mouse mdr3 166 S948A TM 11 Mouse mdr3 166 Y949A TM 11 Mouse mdr3 166 C952A TM 11 Mouse mdr3 166 F953A TM 11 Mouse mdr3 166 F983A TM 12 Human MDR1 169 L975A, V981A, F983A TM 12 Human MDR1 169 M986A, V988A, Q990A, TM 12 Human MDR1 169 V991A V981A, F983A TM 12 Human MDR1 169 L975A, F983A TM 12 Human MDR1 169 L975A, V981A TM 12 Human MDR1 169 F978A TM 12 Human MDR1 19 a aa,amino acid; EC, extracellular loop; IC, intracellular loop; TM,transmembrane domain; NBD, nucleotide binding/utilization domain.
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ABCB1 p.Phe978Ala 10331089:47:1959
status: NEW
PMID: 10724034
[PubMed]
Hafkemeyer P et al: "Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers."
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186
Other mutations in close proximity, e.g., F978A and F978S, affect primarily the drug resistance profile of P-gp (Loo and Clarke, 1993).
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ABCB1 p.Phe978Ala 10724034:186:42
status: NEW
PMID: 7665554
[PubMed]
Loo TW et al: "Rapid purification of human P-glycoprotein mutants expressed transiently in HEK 293 cells by nickel-chelate chromatography and characterization of their drug-stimulated ATPase activities."
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65
By contrast, mutant F978A conferred decreased resistance to all drugs.
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ABCB1 p.Phe978Ala 7665554:65:20
status: NEW81 Wild-type (E) and mutants G141V (å), G185V (Ⅺ), G830V (q), F335A (f), and F978A (Ç) P-glycoproteins-(His)10 were purified using Ni-NTA spin columns and reconstituted with sheep brain phosphatidylethanolamine.
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ABCB1 p.Phe978Ala 7665554:81:86
status: NEW83 Mutant F978A, which confers little resistance to vinblastine, colchicine, doxorubicin, or actinomycin D in transfected cells, also showed little drug-stimulated ATPase activity, except at very high concentrations of verapamil (1.04 mol/min/mg of P-glycoprotein at 800 M verapamil).
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ABCB1 p.Phe978Ala 7665554:83:7
status: NEW111 For mutants G141V, G185V, G830V, and F978A, the pattern of drug-stimulated ATPase correlated with their relative drug-resistant profiles in transfected cells.
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ABCB1 p.Phe978Ala 7665554:111:37
status: NEW114 Mutant F978A conferred little resistance to all drug substrates in transfected cells, and the purified protein also showed ex- FIG. 3.
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ABCB1 p.Phe978Ala 7665554:114:7
status: NEW
PMID: 8104183
[PubMed]
Loo TW et al: "Functional consequences of phenylalanine mutations in the predicted transmembrane domain of P-glycoprotein."
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119
Functional Consequencesof Other Changes to Phe-335 and Phe-978"Mutation of either Phe-335 or Phe-978 to alanine had aprofound effecton the ability of P-glycoprotein to confer resistance to various cytotoxic compounds.
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ABCB1 p.Phe978Ala 8104183:119:93
status: NEW183 0,wild-type;0,mutant Phe-335+Ala;W, mutant Phe-978 to Ala.
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ABCB1 p.Phe978Ala 8104183:183:43
status: NEW
PMID: 8639515
[PubMed]
Hanna M et al: "Mutagenesis of transmembrane domain 11 of P-glycoprotein by alanine scanning."
No.
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32
Finally, elegant studies of Loo and Clarke, in which proline and phenylalanine residues located within TM domains (Loo & Clarke, 1993a,b) as well as glycines in cytoplasmic loops of human MDR1 were systematically replaced by alanines (Loo & Clarke, 1994a), identified several residues within TM 4 (P223A), TM 6 (F335A), TM 10 (P866A), and TM 12 (F978A) and in the intervening cytoplasmic loops where mutations differentially affect the capacity of P-gp to confer resistance to vinblastine (VBL), adriamycin (ADR), colchicine (COL), and actinomycin D (ACT).
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ABCB1 p.Phe978Ala 8639515:32:346
status: NEW
PMID: 9819232
[PubMed]
Hafkemeyer P et al: "Contribution to substrate specificity and transport of nonconserved residues in transmembrane domain 12 of human P-glycoprotein."
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19
Replacement of the conserved residues (for example, F978A) within the TM regions has profound effects on the substrate specificity and transport function of Pgp (11).
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ABCB1 p.Phe978Ala 9819232:19:52
status: NEW
PMID: 16545467
[PubMed]
Shilling RA et al: "New light on multidrug binding by an ATP-binding-cassette transporter."
No.
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58
Although mutation of only one of these residues (L975A, V981A and F983A) has no effect on the phenotype of the protein [20], double mutations either completely inhibit (V981A/F983A and L975A/V981A) or cause 50% inhibition (L975A/F983A) of Table 1.
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ABCB1 p.Phe978Ala 16545467:58:674
status: NEWX
ABCB1 p.Phe978Ala 16545467:58:773
status: NEW59 Published mutations in human and murine P-glycoprotein that alter drug transport in cells Location of mutation Mutation Refs Mutation Refs Mutation Refs Transmembrane helices H61A and others [14] I214L [60] L868W [59] G64R [15] P223A [65] I936A [21] L65R [15] S224P [60] F938A [21] Q139[H/P/R] [60] I306R [18] S939[A/C/T/Y/W/D/F] [21,22] G141V [17] F335A [16] T941A [21] G185V [61,62] V338A [66] Q942A [21] I186N [61] G338A [67,68] A943G [21] G187V [17] A339P [67,68] Y946A [21] G187E [60] G341A [66] S948A [21] A192T [60] S344[A/T/C/Y] [66] Y949A [21] F200L [60] N350I [19] C952A [21] F204S [60] P709A [65] F953A [21] R206L [60] G830V [17] L975A [20] W208G [60] I837L [23] F978A [16] K209E [60] N839I [23] V981A [20] L210I [60] I862F [19] F983A [20] T211P [60] L865F [19] F978A [16] V213A [60] P866A [65] N988D [59] Intracellular domain T169I [60] K177I [60] G288V [17] R170L [60] E180G [60] A931T [19] L171P [60] G181R [60] F934A [21] T172P [60] G183D [60] G935A [21] S176P [60] D184N [60] NBD D555N [63] K1076M [69] E1197Q [64] D558N [64] D1093N [64] D1203N [64] D592N [64] E1125Q [64] D1237N [64] E604Q [64] S1173A [70] E1249Q [64] Review TRENDS in Pharmacological Sciences Vol.27 No.
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ABCB1 p.Phe978Ala 16545467:59:674
status: NEWX
ABCB1 p.Phe978Ala 16545467:59:773
status: NEW
PMID: 11428917
[PubMed]
Hrycyna CA et al: "Molecular genetic analysis and biochemical characterization of mammalian P-glycoproteins involved in multidrug resistance."
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Comment
27
List of mutations in human, mouse and hamster P-gp`s that affect substrate specificity f aaa Mutation Regionb Sourcec Reference aa 78-97 EC 1 human MDR1 78 (ABC20)d Q128He TM 2 mouse mdr3 79 R138H IC 1 mouse mdr3 79 Q139H, R IC 1 mouse mdr3 79 G141V IC 1 human MDR1 25,80 Q145H IC 1 mouse mdr3 79 E155G, K IC 1 mouse mdr3 79 F159I IC 1 mouse mdr3 79 D174G IC 1 mouse mdr3 79 S176F, P IC 1 mouse mdr3 79 K177I IC 1 mouse mdr3 79 N179S IC1 mouse mdr3 79 N183S/G185V IC 1 human MDR1 81 G183D IC1 mouse mdr3 79 G185V IC 1 human MDR1 82-84 G187V IC 1 human MDR1 80 A192T TM 3 mouse mdr3 79 F204S EC 2 mouse mdr3 79 W208G EC 2 mouse mdr3 79 K209E EC 2 mouse mdr3 79 L210I TM 4 mouse mdr3 79 T211P TM 4 mouse mdr3 79 I214T TM 4 mouse mdr3 79 P223A TM 4 human MDR1 85 K285T IC 2 human MDR1 1 G288V IC 2 human MDR1 80 I299M, T319S, L322I, TM 5, EC3, IC 3 human MDR1 86 G324K, S351N V334 TM 6 human MDR1 1 F335A TM 6 human MDR1 25 F335 TM 6 human MDR1 87 V338A TM 6 human MDR1 88 G338A, A339P TM 6 hamster PGY 1 89,90 A339P TM 6 hamster PGY 1 90 G341V TM 6 human MDR1 88 K536R,Q N-NBD human MDR1 91 ERGA→DKGT N-NBD mouse mdr3 92 (aa 522-525) T578C N-NBD mouse mdr3 92 G812V IC 4 human MDR1 80 G830V IC 4 human MDR1 25,80 P866A TM 10 human MDR1 85 F934A TM 11 mouse mdr3 93 G935A TM 11 mouse mdr3 93 I936A TM 11 mouse mdr3 93 F938A TM 11 mouse mdr3 93 S939A TM 11 mouse mdr3 93 S939F TM 11 mouse mdr3 94,95 S941F TM 11 mouse mdr1 94,95 T941A TM 11 mouse mdr3 93 Q942A TM 11 mouse mdr3 93 Table 1-continued aaa Mutation Regionb Sourcec Reference A943G TM 11 mouse mdr3 93 Y946A TM 11 mouse mdr3 93 S948A TM 11 mouse mdr3 93 Y949A TM 11 mouse mdr3 93 C952A TM 11 mouse mdr3 93 F953A TM 11 mouse mdr3 93 F983A TM 12 human MDR1 96 L975A, V981A, F983A TM 12 human MDR1 96 M986A, V988A, TM 12 human MDR1 96 Q990A, V991A V981A, F983A TM 12 human MDR1 96 L975A, F983A TM 12 human MDR1 96 L975A, V981A TM 12 human MDR1 96 F978 TM 12 human MDR1 1 F978A TM 12 human MDR1 25 a aa, amino acid.
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ABCB1 p.Phe978Ala 11428917:27:1936
status: NEWX
ABCB1 p.Phe978Ala 11428917:27:1943
status: NEW
No.
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100
The other group consists of mutations Pro223-to-Ala 46 in TM4; Gly341-to-Val 40 in TM6; Pro866-to-Ala 46 in TM10; Phe978-to-Ala 39 in TM12; Ser939-to-Phe, Tyr949-to-Ala, and Phe953-to-Ala in TM11 of mouse mdr1;42,44 and Ser941-to-Phe 43 in TM11 of mouse mdr3.
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ABCB1 p.Phe978Ala 9441945:100:114
status: NEW
No.
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Comment
67
These included F335A~ which gave considerable increase in ATPase, and F978A which gave large decrease.
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ABCB1 p.Phe978Ala 8549739:67:70
status: NEW