ABCMdb

ABCC1 p.Ile441Leu

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Publications

PMID: 18775981 [PubMed] Grant CE et al: "Structural determinants of substrate specificity differences between human multidrug resistance protein (MRP) 1 (ABCC1) and MRP3 (ABCC3)."

No. Sentence Comment

138 The most dramatic reduction in transport was found for one double mutation located in the G1 region, Y440F/I441L, which reduced LTC4 transport to less than 20% of wild-type levels (Fig. 3B). Login to comment
142 With the exception of one triple mutation, in which substitution of M443 with L was introduced into the LTC4 transport-deficient Y440F/I441L double mutant, no combination of mutations tested reduced LTC4 transport by more than 60 to 70% (data not shown). Login to comment
143 The Y440F/I441L/M443L virtually eliminated LTC4 transport (Fig. 3B) but also reduced E217betaG transport by approximately 80% (Fig. 3C). Login to comment
144 Transport of LTC4, E217betaG, E13SO4, and MTX by Y440F, I441L, and M443L MRP1 Mutant Proteins. Login to comment
156 The Y440F and M443L mutations each independently decreased initial rates of LTC4 transport by approximately 60 and 50%, respectively, whereas the I441L mutation had little or no effect (Fig. 3B). Login to comment
157 In contrast, E217betaG transport was decreased approximately 50% by both the I441L and M443L mutations but only 20% by the Y440F mutation (Fig. 3C). Login to comment
158 All three mutations significantly decreased E13SO4 transport in the presence of 2 mM S-methyl GSH, with the Y440F, I441L, and M443L mutations reducing transport at 1 min by approximately 65, 50, and 90%, respectively (Fig. 3D). Login to comment
175 Kinetic Parameters of [3 H]LTC4 Transport by Y440F and I441L Single and Double Mutants. Login to comment
176 We also determined the effects of the Y440F and I441L single and double mutations on the Km and Vmax for LTC4 transport. Login to comment
179 Although LTC4 transport by the I441L mutant was only marginally decreased at a fixed concentration of substrate, linear regression analysis indicated that the Km for LTC4 was increased approximately 2-fold (149 nM for the I441L mutant protein versus 72 nM for wild-type MRP1), again with no significant change in Vmax (normalized Vmax for the I441L mutation 42 versus 37 pmol/mg/min for the wild-type protein) (Fig. 4, A and B). Login to comment
200 Photolabeling of both fragments of the I441L mutant protein, which displayed only a 2-fold increase in Km, was essentially indistinguishable from that obtained with the wild-type MRP1 protein. Login to comment
201 However, photolabeling of the NH2-terminal fragments of both the Y440F and double Y440F/I441L mutant proteins was similarly, substantially reduced compared with both the wild-type and the I441L mutant. Login to comment
203 Furthermore, photolabeling of the COOH-terminal fragment of the Y440F and Y440F/I441L mutant proteins was also reduced when compared with wild-type MRP1 or the I441L mutant, despite the fact that this region is identical in all four proteins. Login to comment
222 Shown are wild-type MRP1 (f), Y440F (Œ), I441L (), and Y440F/I441L (ࡗ). Login to comment
226 [3 H]LTC4 photolabeling of membrane vesicle isolated from Sf21 cells expressing wild-type and mutant MRP1 proteins. A, immunoblot showing the relative amounts of MRP1 protein in each sample after adjustment for relative MRP1 protein expression; wild-type MRP1 (35 ␮g) and mutants Y440F (75 ␮g), I441L (22 ␮g), and Y440F/I441L (20 ␮g). Login to comment
238 In contrast, the I441L mutant protein, which decreased S-methyl GSH-stimulated transport of E13SO4 by 55% compared with wild-type MRP1 (Fig. 3D), bound approximately equivalent levels of azidophenacyl-[35 S]GSH (Fig. 7C), suggesting that, as was determined for LTC4, the affinity for azidophenacyl-GSH is relatively unaffected by the I441L mutation. Login to comment
242 Effect of the Y440F, I441L, M443L, and Y440F/I441L Mutations on Resistance to Vincristine, Doxorubicin, and VP-16. Login to comment
243 Lastly, the drug-resistance profiles of Y440F, I441L, M443L, and Y440F/I441L mutant proteins were examined because unlike MRP1, the profile of resistance to natural product drugs conferred by MRP3 is restricted primarily to epipodophyllotoxins (Deeley et al., 2006). Login to comment
295 In contrast to the Y440F mutation, the conservatively substituted I441L mutation had no effect on LTC4 or MTX transport but decreased transport of both E217betaG and E13SO4, whereas the M443L mutation decreased transport of all three conjugated substrates but not TABLE 2 Relative Drug Resistance of HEK293 Cells Transfected with Wild-Type and Mutant MRP1 Transfectant Drug (Relative Resistance Factora ) Vincristine VP-16 Doxorubicin HEKMRP1 15.6 Ϯ 2.5 16.2 Ϯ 4.9 4.5 Ϯ 0.3 HEKMRP1-Y440F 2.4 Ϯ 0.5 (5.1) 2.7 Ϯ 0.8 (6.0) 1.3 Ϯ 0.2 (1.9) HEKMRP1-1441L 8.9 Ϯ 2.5 (9.7) 4.1 Ϯ 1.2 (4.4) 3.7 Ϯ 1.4 (4.1) HEKMRP1-M443L 6.5 Ϯ 1.2 (6.0) 5.8 Ϯ 0.5 (5.4) 3.8 Ϯ 0.7 (3.6) HEKMRP1-Y440F/1441L 3.9 Ϯ 1.0 (7.5) 1.3 Ϯ 0.3 (1.7) 1.2 Ϯ 0.2 (1.5) HEKMRP3 1.1 Ϯ 0.1 6.4 Ϯ 1.9 0.87 Ϯ 0.2 a The relative resistance factor was obtained by dividing the IC50 values for the wild-type or mutant MRP1-transfected cells by the IC50 value for cells transfected with the expression vector alone. Login to comment

PMID: 21143116 [PubMed] He SM et al: "Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1)."

No. Sentence Comment

794 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