ABCMdb

PMID: 21143116

He SM, Li R, Kanwar JR, Zhou SF
Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1).
Curr Med Chem. 2011;18(3):439-81., [PubMed]

Sentences

No. Mutations Sentence Comment

335 ABCC2 p.Leu23Arg ABCC2 p.Leu23Pro Some other NSAIDs including sulindac were found to have a similar effect in human lung cancer cell lines DLKP, A549, COR L23P and COR L23R and in a human leukaemia line HL60/ADR [229], although it is unrelated to the action of these drugs on cyclooxygenases. Login to comment 654 ABCC1 p.Asp793Glu ABCC1 p.Glu1455Asp The Asp793Glu mutation in NBD1 enhanced its hydrolytic capacity, whereas the Glu1455Asp mutation in NBD2 resulted in an increased affinity of NBD2 for ATP, but a decreased hydrolytic activity [322]. Login to comment 671 ABCC1 p.Asp793Glu The Asp793Glu mutant of NBD1 showed increased hydrolytic capacity but had occlusion of the resultant ADP in the absence of vanadates [322]. Login to comment 673 ABCC1 p.Glu1455Asp The Glu1455Asp mutant with a reciprocal mutation of NBD2 exhibited an increased affinity for both azido-ATP and -ADP. Login to comment 711 ABCC1 p.Glu1089Gln More NH2-proximal regions of TMD1 also appear to be involved in LY475776 binding since tryptic fragments corresponding to TM12/13 and TM14/15 are photolabeled, and photolabeling is reduced in the Glu1089Gln mutant of TM14 [270, 271]. Login to comment 720 ABCC1 p.Trp222Leu ABCC1 p.Trp223Leu ABCC1 p.Arg230Ala Membrane vesicles prepared from cells expressing mutated MRP1/ABCC1 at Trp222Leu, Trp223Leu, or Arg230Ala within L0 could transport SN-38 (active metabolite of irinotecan), but not LTC4 or E217 G which are transported by MRP1/ABCC1 in a GSH-dependent manner, and could not be photolabeled with 11-azidophenyl agosterol A [279]. Login to comment 726 ABCC1 p.Glu1144Ala ABCC1 p.Asp1179Ala ABCC1 p.Lys1181Ala ABCC1 p.Arg1166Ala These include Cys43 in TM1 [171], Thr73 in CL1 [366], Trp222 in L0 [279], Trp223 in L0 [279], Arg230 in L0 [279], Trp261 in L0 [271, 302, 338], Lys267 in L0 [271, 302, 338], Lys319 in TM6 [339], Tyr324 in TM6 [301], Lys332 in TM6 [166, 339-341], His335 in TM6, Asp336 in TM6 [339], Lys347 in TM6 [339], Lys396 in TM7 [339], Arg433 in TM8 [363], Asp436 in TM8 [339], Trp445 in TM8, Trp459 in TM8, Pro478 in TM9, Thr550 in TM10 [343], Trp553 in TM10 [344], Thr556 in TM10 [343], Pro557 in TM10 [345], Tyr568 in TM10 [343], Arg593 in TM11 [339], Phe594 in TM11 [300], Asn597 in TM11, Ser604 in TM11, Ser605 in TM11, Trp653 in NBD1 [351], Lys684 in Walker A motif of NBD1 [350, 364], Ser685 in Walker A motif of NBD1 [353], Arg723 in NBD1 [366], Gly771 in the ABC signature (C motif) of NBD1 [364], Asp792 in Walker B motif of NBD1 [361], Asp793 in Walker B motif of NBD1 [353], Ala989 in TM12 [367], Pro1120 in TM13, Pro1121 in TM13, Arg1058 at TM13/CL6 interface [366], Glu1089 in TM14, Lys1092 in TM14, Ser1097 in TM14, Asn1100 in TM14, Arg1138 in TM15 [354], Lys1141 in CL7 [354], Arg1142 in CL7 [354], Glu1144Ala in CL7 [355], Pro1150 in CL7 [345, 347, 348], Arg1166Ala in CL7 [355], Asp1179Ala in CL7 [355], Lys1181Ala in CL7 [355], Asp1183 in CL7 [355], Tyr1189 in CL7 [368], Tyr1190 in CL7 [368], Arg1197 in TM16 [357], Trp1198 in TM16 [344], Arg1202 in TM16 [357], Glu1204 in TM16 [357], Tyr1236 in TM17, Thr1241 in TM17, Thr1242 in TM17, Tyr1243 in TM17, Asn1245 in TM17, Trp1246 in TM17 [166, 339-341], Arg1249 in TM17 [342], Tyr1302 in NBD2 [351], Lys1333 in Walker A motif of NBD2 [350], Gly1433 in the ABC signature motif of NBD2 [352, 364], Glu1455 in Walker B motif of NBD2 [322], and His1486 in NBD2 [349]. Login to comment 735 ABCC1 p.Arg433Ser The naturally occurring replacement of Arg433 by Ser (neutral) at the interface of CL4 and TM8 caused a 2-fold decrease in LTC4 and estrone sulfate transport but were 2.1-fold more resistant to doxorubicin while while resistance to etoposide (VP-16) and vincristine remained unchanged [363]. Login to comment 739 ABCC1 p.Arg1138Glu In contarst, the mutations showed minor to moderate effect on MTX transport, with a maximum decrease for Arg1138Glu). Login to comment 742 ABCC1 p.Lys1141Arg ABCC1 p.Lys1141Glu Notably, mutation of Lys1141 to either Glu or Arg impaired MRP1/ABCC1 expression and routing to the plasma membrane [354]. Login to comment 743 ABCC1 p.Lys1141Arg ABCC1 p.Lys1141Glu ABCC1 p.Lys1141Glu Substitution of Lys1141 with Glu (negatively chages) at TM15/CL7 interface decreased LTC4 transport by 70%, but an Arg substitution (positively charged) at this position did not; GSH transport by both Lys1141Glu and Lys1141Arg mutants was decreased by 40%, suggesting that the presence of a positive charge at Lys1141 was sufficient for LTC4 transport, whereas the less bulky side chain of Lys itself seemed important for GSH transport [354]. Login to comment 744 ABCC1 p.Lys1141Glu ABCC1 p.Arg1138Lys ABCC1 p.Arg1138Glu ABCC1 p.Arg1142Glu ABCC1 p.Arg1142Lys The Arg1138Glu and Lys1141Glu mutants, but not the Arg1138Lys, Arg1142Glu, and Arg1142Lys mutants, showed a >50% decrease in binding to [3 H]LTC4. Login to comment 745 ABCC1 p.Lys1141Arg All mutants except Lys1141Arg showed substantially reduced trapping of 8-azido-[ 32P]ATP (40-60% that of wild-type MRP1), implicating that the ability of these mutants at TM15/CL7 interface to hydrolyze ATP is impaired and consequently disrupt the transport cycle and cause a decrease in transport activity. Login to comment 751 ABCC1 p.Pro51Ala ABCC1 p.Pro42Ala The transport activity of the double mutant Pro42Ala/Pro51Ala was reduced by >80%. Login to comment 755 ABCC1 p.Pro1150Ala Compared with wild-type MRP1/ABCC1, the Pro1150Ala mutant showed decreased LTC4, estrone sulfate, and GSH transport but substantially increased E217 G and MTX transport [345]. Login to comment 757 ABCC1 p.Pro1150Ala In the case of Pro1150Ala mutant, vanadate-induced trapping of [ 32 P]8N3ADP was greatly diminished relative to wild-type MRP1, while photolabeling of this mutant with [ 32 P]8N3ATP under nonhydrolytic conditions remained unchanged [345]. Login to comment 758 ABCC1 p.Pro1150Ala ABCC1 p.Pro1150Leu ABCC1 p.Pro1150Gly ABCC1 p.Pro1150Val ABCC1 p.Pro1150Ile The Pro1150Gly, Pro1150Ile, Pro1150Leu and Pro1150Val mutants exhibited a phenotype similar to the Pro1150Ala mutant with respect to organic anion transport and [ 32 P]8N3ATP photolabeling [347]. Login to comment 763 ABCC1 p.Trp1246Phe In contrast, substitution of Trp1246 with Phe, Tyr, Ala, or Cys selectively eliminated E217 G and NNAL-O-glucuronide transport and drug resistance but showed little or no effect on LTC4 and GSH transport [166, 341, 371]. Login to comment 765 ABCC1 p.Trp1246Cys ABCC1 p.Lys332Leu Both Lys332Leu and Trp1246Cys mutants were as sensitive as wild-type MRP1/ABCC1 to MK-571, LY171883, and the potent MRP1/ABCC1 inhibitor 6-[4 -carboxyphenylthio]-5[S]- hydroxy-7[E], 11[Z]14[Z]-eicosatetrenoic acid (BAY u9773, a leukotriene-like dual antagonist that acts on both CysLT1 and CysLT2 receptors) [341]. Login to comment 766 ABCC1 p.Lys332Leu ABCC1 p.Lys332Leu MK-571 and LY171883 were moderately (2-fold) less potent inhibitors of E217 G uptake by wild-type MRP1/ABCC1 than by the Lys332Leu mutant, but LY465803 showed 16-fold greater potency to inhibit wild-type compared with Lys332Leu mutant. Login to comment 767 ABCC1 p.Lys332Leu In a similar manner, the GSH derivative S-decyl-GSH and GSSG inhibited wild-type MRP1/ABCC1 activity with IC50 >100-fold and >30-fold lower than for Lys332Leu, respectively [341]. Login to comment 768 ABCC1 p.Trp1246Cys ABCC1 p.Lys332Leu In contrast to its more potent inhibitory effect on E217 G transport by the Lys332Leu mutant, MK-571 was a less potent inhibitor ( 3-fold) of LTC4 transport by the Trp1246Cys mutant than by wild-type MRP1. Login to comment 769 ABCC1 p.Trp1246Cys ABCC1 p.Lys332Leu However, similar to Lys332Leu, the inhibitory potency of BAY u9773 for LTC4 transport by wild-type and Trp1246Cys was comparable. Login to comment 781 ABCC1 p.Trp361Ala Ala substitution of Trp361 in TM7 and Trp459 in TM9 only resulted in more moderate changes in trasnport activity. Login to comment 792 ABCC1 p.Tyr440Phe The Tyr440Phe mutant expressed in Sf21 cells showed a 5-fold higher Km for LTC4 and substantially reduced photolabeling of MRP1/ABCC1 by both [3 H]LTC4 and the GSH derivative, azidophenacyl-[35 S]GSH [374]. Login to comment 794 ABCC1 p.Tyr440Phe ABCC1 p.Tyr440Phe ABCC1 p.Ile441Leu ABCC1 p.Met443Leu In addition, the Tyr440Phe, Ile441Leu, Met443Leu mutations decreased resistance to vincristine and etoposide 2-to 3-fold, whereas only the Tyr440Phe mutant displayed a major decrease in resistance to doxorubicin [374]. Login to comment 806 ABCC1 p.Lys1141Glu Replacement of Lys1141 with Glu also impaired the expression of MRP1/ABCC1 at the plasma membrane and reduced its transport activity. Login to comment 807 ABCC1 p.Gly1161Pro ABCC1 p.Glu1157Leu The double-mutant Glu1157Leu/Gly1161Pro showed no activity for LTC4 and was not labeled by the photoaffinity ligand azidoAgosterol A [365]. Login to comment 809 ABCC1 p.Asp1183Ala ABCC1 p.Arg1166Ala The Arg1166Ala and Asp1183Ala/Glu mutants were poorly expressed, probably by affecting the proper folding of the protein during its biosynthesis. Login to comment 813 ABCC1 p.Glu1144Ala ABCC1 p.Asp1179Ala ABCC1 p.Lys1181Ala The single mutants Glu1144Ala, Asp1179Ala, and Lys1181Ala) and the triple mutant 1169AAQA showed only moderate and substrate-selective changes in transport activity [355]. Login to comment 816 ABCC1 p.Cys43Ser ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile ABCC1 p.Arg1058Gln ABCC1 p.Gly671Val ABCC1 p.Arg433Ser ABCC1 p.Cys1047Ser ABCC1 p.Val353Met ABCC1 p.Ala989Thr ABCC1 p.Ser92Phe ABCC1 p.Arg230Asn ABCC1 p.Val1146Ile ABCC1 p.Thr1401Met ABCC1 p.Thr1337Ala ABCC1 p.Ala861Thr There are at least 15 naturally occurring mutations identified in MRP1/ABCC1, including Cys43Ser in TM1, Thr73Ile in CL1, Ser92Phe in TM2, Arg230Asn in L0, Val353Met at TM6/TM7 interface, Arg433Ser in TM8, Gly671Val in TM11, Arg723Gln located between the Walker A and Walker B motifs of NBD1, Ala861Thr at NBD1/TM12 interface, Ala989Thr in TM12, Cys1047Ser in TM13, Arg1058Gln in CL7, Val1146Ile in CL7, Thr1337Ala between the Walker A and Walker B motifs of NBD2, and Thr1401Met, and many of them have been found to affect its transport activity [171, 362, 363, 366, 367, 377-384]. Login to comment 818 ABCC1 p.Cys43Ser The Cys43Ser mutant in TM1 (128G>C in exon 2) exhibited impaired plasma membrane location of the transporter, with a 2.5-fold decrease in arsenite resistance and a lower vincristine resistance [171]. Login to comment 819 ABCC1 p.Arg433Ser A naturally-occurring mutation of 1299G>T in exon 10 causing Arg433Ser in TM8 of TMD1 resulted in decreased transport of LTC4 and increased resistance to doxorubicin [363]. Login to comment 820 ABCC1 p.Cys43Ser ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile ABCC1 p.Arg1058Gln When Cys43Ser, Thr73Ile, Arg723Gln, and Arg1058Gln were separately transfected in CHO-K1 or HEK293 cells, the cells displayed altered resistance profiles to a panel of anticancer drugs compared to the wild-type [366]. Login to comment 821 ABCC1 p.Arg723Gln In HEK293 cells, Arg723Gln confers lower resistance to all drugs compared with wild-types. Login to comment 822 ABCC1 p.Arg723Gln In CHO-K1 cells, Arg723Gln significantly decreased resistance to all drugs tested except cisplatin, paclitaxel and MTX. Login to comment 823 ABCC1 p.Arg1058Gln The Arg1058Gln mutant showed a significant decrease in resistance to anthracyclines and etoposide in HEK293 cells [366]. Login to comment 824 ABCC1 p.Arg1058Gln In CHO-K1 cells, the Arg1058Gln mutant conferred a lower resistance to vinblastine, anthracyclines, etoposide and MTX. Login to comment 825 ABCC1 p.Thr73Ile In HEK293 cells, the Thr73Ile mutation displayed a lower resistance to vincristine and MTX [366]. Login to comment 828 ABCC1 p.Arg723Gln ABCC1 p.Thr73Ile For example, the frequencies of the Arg723Gln A allele and the Thr73Ile T allele in Chinese population were higher than the Caucasians [366]. Login to comment