ABCB1 p.Leu65Arg
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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.Leu65Arg 10331089:47:220
status: NEW
PMID: 17848563
[PubMed]
Loo TW et al: "Suppressor mutations in the transmembrane segments of P-glycoprotein promote maturation of processing mutants and disrupt a subset of drug-binding sites."
No.
Sentence
Comment
7
The presence of arginine residues reduced the apparent affinity of P-gp for vinblastine (L65R, T199R, and I306R), cyclosporin (I306R and F343R), or rhodamine B (F343R) by 4-60-fold.
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ABCB1 p.Leu65Arg 17848563:7:89
status: NEW69 For disulfide cross-linking analysis, the cDNA of mutant L339C(TM6)/ F728C(TM7) (34) was modified to also encode the L65R, T199R, I306R, or F343R mutations.
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ABCB1 p.Leu65Arg 17848563:69:117
status: NEW164 Effect of L65R and T199R Mutations on Maturation of a P-gp Processing Mutant-We then tested whether arginines introduced into TM1 (Leu65 ) (27) or TM3 (Thr199 ) promoted maturation of a P-gp processing mutant.
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ABCB1 p.Leu65Arg 17848563:164:10
status: NEW204 Effect of L65R Mutation on Protease Sensitivity of P-gp-In a previous study (37), we observed that expression of P-gp processing mutants in the presence of drug substrates appeared to convert the protein from a loosely folded conformation to a more compact structure because they became about 100-fold more resistant to trypsin.
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ABCB1 p.Leu65Arg 17848563:204:10
status: NEW229 These results indicate that the L65R mutation converts mutant G251V into a more protease-resistant conformation.
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ABCB1 p.Leu65Arg 17848563:229:32
status: NEW234 For example, the L65R mutation only caused a large reduction (57-fold) in the apparent affinity for vinblastine and little change in affinities for cyclosporin A or rhodamine B.
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ABCB1 p.Leu65Arg 17848563:234:17
status: NEW270 By contrast, the ATPase activity of mutant L65R was activated by treatment with MTS-verapamil (27) but not by MTS-rhodamine (Ͻ2-fold activation after treatment with 2 mM MTS-rhodamine) (data not shown).
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ABCB1 p.Leu65Arg 17848563:270:43
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
21
It was found that the L65R mutation promoted maturation of P-gp processing mutants such as ⌬Y490 and G251V (9).
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ABCB1 p.Leu65Arg 18596043:21:22
status: NEW37 Printed in the U.S.A. with a L65R substitution was previously found to be particularly efficient (9).
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ABCB1 p.Leu65Arg 18596043:37:31
status: NEW81 We previously observed that introduction of arginines into TM segments such as L65R (TM1), T199R(TM3), I306R(TM5), and F343R(TM6) promoted maturation of P-gp processing mutants (9).
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ABCB1 p.Leu65Arg 18596043:81:79
status: NEW103 Mutants M68R and L65R showed the highest increase in maturation efficiency (85 and 60% mature 170-kDa mature, respectively) (Fig. 2).
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ABCB1 p.Leu65Arg 18596043:103:17
status: NEW109 The position of the L65R mutation that promotes maturation of P-gp processing mutants is shown as a black ball.
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ABCB1 p.Leu65Arg 18596043:109:20
status: NEW116 The position of Leu-65 (L65R mutation promotes maturation of processing mutants) is shaded in black. about 45%.
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ABCB1 p.Leu65Arg 18596043:116:24
status: NEW149 Mutants L65R and M68R yielded mature 170-kDa P-gp as the major product in the absence of drug substrates.
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ABCB1 p.Leu65Arg 18596043:149:8
status: NEW165 TABLE 1 Effects of drug substrates on the maturation of TM1 arginine mutants containing the G251V mutation Mutation (G251V ؉) No drug Cyclosporin A Verapamil Vinblastine Rhodamine None - 111a,c 111 111 11 V52R -a,b 111 111 111 11 V53R 2 - - - - G64R 2 - - - - T55R 2 - - - - L56R 2 - - - - A57R 2 - - - - A58R 2 - - - - I59R 2 - - - - I60R 2 - - - - H61R - 111 1 1 1 G62R 2 - - - - A63R 2 - - - - G64R 1 111 1 1 11 L65R 11 111 11 11 11 P66R 2 1 - - - L67R - 111 111 111 11 M68R 111 111 111 111 111 M69R - 111 - 11 111 L70R - 111 111 111 11 V71R 1 111 111 111 11 F72R 2 1 1 1 1 a Change in the amount of mature (170 kDa) protein in the presence of drug substrate relative to that in the absence of drug substrate.
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ABCB1 p.Leu65Arg 18596043:165:421
status: NEW172 In a previous cross-linking study we found that introduction of L65R change into mutant L339C(TM6)/ F728C(TM7) reduced its apparent affinity for vinblastine by about 60-fold but had little effect on P-gp interactions with cyclosporin A or rhodamine B (9).
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ABCB1 p.Leu65Arg 18596043:172:64
status: NEW183 The G64R, L65R, and M68R mutations preferentially affected P-gp-vinblastine interactions.
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ABCB1 p.Leu65Arg 18596043:183:10
status: NEW208 Effect of TM11 Mutations on Rescue of Mutant G251V Containing the L65R and M68R Changes-One reason that Arg-68 caused the largest increase in maturation of mutant G251V is that the arginine residue may promote packing of the TM segments.
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ABCB1 p.Leu65Arg 18596043:208:66
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.Leu65Arg 18596043:220:12
status: NEWX
ABCB1 p.Leu65Arg 18596043:220:158
status: NEW
PMID: 9287132
[PubMed]
Taguchi Y et al: "Amino acid substitutions in the first transmembrane domain (TM1) of P-glycoprotein that alter substrate specificity."
No.
Sentence
Comment
43
Cells transfected with Gly64 -> Arg, or Leu65 -> Arg cDNAs were selected with stepwise increasing concentrations (5, 10, 20 ng/ml) of vinblastine and finally maintained in 20 ng/ ml vinblastine.
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ABCB1 p.Leu65Arg 9287132:43:40
status: NEW55 From cells transfected with the wild type and He60 -> Arg, His61 -> Arg, Ala63 -> Arg, Gly64 -> Arg, or Leu65 -> Arg mutant cDNA, both Vbl- and Col-resistant colonies were obtained (Fig. 1).
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ABCB1 p.Leu65Arg 9287132:55:104
status: NEW58 Noticeably, cells transfected with mutant Gly64 -> Arg or Leu65 -> Arg yielded comparable number of Col-resistant colonies, but much less Vbl-resistant colonies, suggesting that the substrate specificities of these two mutants were altered from that of the wild type.
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ABCB1 p.Leu65Arg 9287132:58:58
status: NEW68 Membrane proteins were obtained from stable transformants maintained in 20 ng/ml vinblastine for mutants Gly64 -»Arg and Leu65 -> Arg, or 30 ng/ml vinblastine for wild type and the other mutants.
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ABCB1 p.Leu65Arg 9287132:68:126
status: NEW74 The drug-resistance profiles of the cells expressing He60 -> Arg, His61 -»Arg, Ala63 -»Arg, Gly64 -> Arg, and Leu65 -> Arg mutant P-glycoproteins were investigated by comparing their relative resistance to Vbl, Col, VP16, and Adr (Fig. 3).
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ABCB1 p.Leu65Arg 9287132:74:120
status: NEW75 The drastic alterations in the drug resistance profile were observed with Gly64 -> Arg or Leu65 -> Arg mutant as well as His61 -»Arg mutant.
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ABCB1 p.Leu65Arg 9287132:75:90
status: NEW82 From each of membrane fraction, a band migrating at about 170 kDa was detected, indicating that He60 -> Arg, His61 -»Arg, Ala63 -»Arg, Gly64 -»Arg, and Leu65 -> Arg mutant P-glycoproteins were normally processed and expressed in the plasma membrane.
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ABCB1 p.Leu65Arg 9287132:82:167
status: NEW89 The mutant P-glycoproteins, in which either He60 , Ala63 , Gly64 , or Leu65 was replaced by Arg were successfully expressed in the plasma membrane of KB3-1 cells and were functional as drug transporters as the His61 mutants.
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ABCB1 p.Leu65Arg 9287132:89:70
status: NEW90 The substrate specificities of Gly64 -»Arg and Leu65 -> Arg mutant P-glycoproteins were quite different from that of the wild type, and similar to that of His61 -»Arg mutant, while He60 and Ala63 -> Arg mutant P-glycoproteins showed similar substrate specificities to that of the wild-type P-glycoprotein.
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ABCB1 p.Leu65Arg 9287132:90:52
status: NEW92 The similarity among the substrate specificities of Gly64 -> Arg, Leu65 -> Arg, and His61 -> Arg mutant P-glycoproteins suggest that the amino acid residues at position 64 and 65 are also important in deciding the substrate specificity.
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ABCB1 p.Leu65Arg 9287132:92:66
status: NEW106 The substrate specificities of the Gly64 -> Arg and Leu65 -> Arg mutants were similar to, but not exactly same with that of the His61 -> Arg mutant.
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ABCB1 p.Leu65Arg 9287132:106:52
status: NEW107 The cells expressing Gly64 -> Arg or Leu65 -> Arg mutant were more resistant to VP16 than to Vbl, while cells expressing the His61 -* Arg mutant were more resistant to Vbl than to VP16 (Fig. 3).
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ABCB1 p.Leu65Arg 9287132:107:37
status: NEW
PMID: 26507655
[PubMed]
Loo TW et al: "Mapping the Binding Site of the Inhibitor Tariquidar That Stabilizes the First Transmembrane Domain of P-glycoprotein."
No.
Sentence
Comment
175
In the N-terminal TMD1 domain, the largest number of arginine mutations predicted to line the drug-binding pocket that inhibited tariquidar rescue were located in TM1 (H61R, G64R, L65R, M68R, M69R, and F72R) and TM5 (F303R, I306R, Y307R, S309R, and Y310R) (Fig. 4, A and E).
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ABCB1 p.Leu65Arg 26507655:175:180
status: NEW193 It was found that 16 of the 28 mutants resembled the G251V/I868R mutant as expression in the presence of 5 òe;M cyclosporine A yielded mature P-gp as the major product in TM1 (H61R, G64R, L65R, M68R, and M69R), TM5 (F303R, I306R, and S309R), TM7 (Q725R and F728R), TM10 (I868R and G872R), TM11 (F942R, T945R, and Q946R), and TM12 (V982R) (Fig. 7).
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ABCB1 p.Leu65Arg 26507655:193:192
status: NEW283 We identified 13 additional arginine mutations (H61R, G64R, L65R, and M68R in TM1; A129R in TM2; I306R and S309R in TM5; F343R in TM6; F942R, T945R, Q946R, and Y950R in TM11; and L975R in TM12) (Fig. 11A) that were not predicted to lie within 4.5-&#c5; of the predicted site 3 tariquidar-binding site (9).
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ABCB1 p.Leu65Arg 26507655:283:60
status: NEW313 Therefore, arginines predicted to lie outside of the tariquidar-binding site in TM1 and TM11 in the docking studies (H61R, G64R, L65R, and M68 in TM1; F942R, T945R, Q946R, and Y950R in TM11) might alter interactions between TM1 and TM11.
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ABCB1 p.Leu65Arg 26507655:313:129
status: NEW