ABCMdb

ABCB1 p.Phe335Ala

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Publications

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. Login to comment

PMID: 10400654 [PubMed] Vo QD et al: "Identification of P-glycoprotein mutations causing a loss of steroid recognition and transport."

No. Sentence Comment

310 A F335A or F335S change caused increased resistance to doxorubicin. Login to comment

PMID: 16456713 [PubMed] Loo TW et al: "Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux."

No. Sentence Comment

96 For example, mutation of Pro223 to alanine in TM 4 decreased the affinity of P-gp for colchicine but not vinblastine (Loo & Clarke, 1993b) while mutation of Phe335 to alanine decreased the affinity of P-gp for vinblastine but not for colchicine (Loo & Clarke, 1993a, 1994b). Login to comment

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."

No. Sentence Comment

64 For example, mutants G141V or G830V conferred increased resistance to colchicine (about 3-fold) relative to that of wild-type enzyme while mutant F335A conferred decreased resistance to vinblastine. Login to comment
81 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. Login to comment
88 The basal ATPase activity of mutant F335A was also about 3-fold higher (0.32 ␮mol/min/mg of P-glycoprotein) than that of wild-type enzyme (0.11 ␮mol/ min/mg of P-glycoprotein). Login to comment
126 Purified mutant F335A P-glycoprotein, however, showed large increases in ATPase activity in the presence of all three drug substrates but conferred decreased relative resistance to vinblastine and only a small increase in resistance to colchicine in transfected cells (Loo and Clarke, 1993b). Login to comment
127 One explanation for this discrepancy is that mutation F335A alters the dissociation of vinblastine from P-glycoprotein such that the enzyme is slow in effluxing vinblastine. Login to comment
129 These possibilities could explain the fact that purified mutant F335A has a higher basal as well as drug-stimulated ATPase activity compared with wild-type enzyme. Login to comment

PMID: 8104183 [PubMed] Loo TW et al: "Functional consequences of phenylalanine mutations in the predicted transmembrane domain of P-glycoprotein."

No. Sentence Comment

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. Login to comment
134 Mutation of Phe-335 to Ala orSer actually reversed the preferential resistance of P-glycoprotein to vinblastine relative to colchicine. Login to comment
135 A vinblastine/colchicine ratio of 4.1 was obtained for the wild-type enzyme, whereas mutants Phe335 to Ala or Ser hadvalues of 0.59and 0.44respectively. Login to comment
160 Vinblastine Phe335-->Ala Wild-type -->Leu -->Ser Phe978-->Ah -->Tyr -->Ser ">Leu -->Tyr Colchicine 1 Adriamycin Actinomycin D 0.5 1 1.5 0.5 1 1.5 0.5 1 1.5 0.5 1 1.5 Relative Resistance FIG. 5. Comparision of relative resistances of stable cell lines expressing mutants Phe-335or Phe-978 +Ala, Ser, Leu, or Tyr. Login to comment
179 100 F335A -80 60 40 20 0 ' 1I I I I 10 100 1000 Vinblastine(ug/ml) FIG.7. Login to comment
243 It has been found that mutations of Pro-223 toAla, Pro-866 toAla (Loo and Clarke, 1993), Phe-978 toAla or Ser (this study), and Ser-941 to Phe (Groset al., 1991) yield proteins that have reduced ability to conferresistanceto colchicine butretainthecapacity to conferresistancetovinblastine.The oppositeeffect is observed for mutation of Phe-335 to Ala or Ser (this study) or Gly-185 to Val (Choi et al., 1988). Login to comment

PMID: 8639515 [PubMed] Hanna M et al: "Mutagenesis of transmembrane domain 11 of P-glycoprotein by alanine scanning."

No. Sentence Comment

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). Login to comment

PMID: 16545467 [PubMed] Shilling RA et al: "New light on multidrug binding by an ATP-binding-cassette transporter."

No. Sentence Comment

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. Login to comment
59 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. Login to comment

PMID: 11428917 [PubMed] Hrycyna CA et al: "Molecular genetic analysis and biochemical characterization of mammalian P-glycoproteins involved in multidrug resistance."

No. Sentence 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. Login to comment

PMID: 9711563 [PubMed] Greenberger LM et al: "Identification of drug interaction sites in P-glycoprotein."

No. Sentence Comment

199 Furthermore, alterations in photoaffinity labeling were observed with the F335A mutants.3° This does not exclude the fact that other regions in P-glycoprotein play a functional role in drug binding or transport. Login to comment

PMID: 9441945 [PubMed] Ueda K et al: "How does P-glycoprotein recognize its substrates?"

No. Sentence Comment

98 The effects of amino acid substitutions on substrate specificity of P-glycoprotein can generally be classified into two groups.46 The first group is of mutations Gly185-to-Val, 51,52 Gly141-to-Val, and Gly187- to-Val,54 all in the first cytoplasmic loop; Gly288-to- Val54 in the second cytoplasmic loop; Phe335-to-Ala 39 and Val338-to-Ala 40 in TM6; Gly812-to-Val and Gly830-to-Val 54 in the fourth cytoplasmic loop. Login to comment

PMID: 24624364 [PubMed] Sharom FJ et al: "Complex Interplay between the P-Glycoprotein Multidrug Efflux Pump and the Membrane: Its Role in Modulating Protein Function."

No. Sentence Comment

169 This structure is compatible with decades of biochemical analysis on the human protein, and helps to explain perplexing functional data on the Phe335Ala mutant. Login to comment