ABCMdb

ABCC1 p.Tyr1243Phe

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Publications

PMID: 11925441 [PubMed] Zhang DW et al: "Determinants of the substrate specificity of multidrug resistance protein 1: role of amino acid residues with hydrogen bonding potential in predicted transmembrane helix 17."

No. Sentence Comment

2 To determine whether other residues with hydrogen bonding potential within TM17 influence substrate specificity, we replaced Ser1233 , Ser1235 , Ser1237 , Gln1239 , Thr1241 , and Asn1245 with Ala and Tyr1236 and Tyr1243 with Phe. Login to comment
5 Mutation Y1243F reduced resistance to all drugs tested by 2-3-fold. Login to comment
8 Only mutation Y1243F altered the ability of MRP1 to transport both leukotriene 4 and E217betaG. Login to comment
113 Mutation of one polar-aromatic residue, Y1243F, caused an approximately 2-3-fold reduction of resistance to all four drugs, whereas three mutations, Y1236F, T1241A, and N1245A, resulted in a 2-3-fold loss of resistance to only certain drugs. Login to comment
117 Subcellular Localization of Mutant and Wild Type MRP1 in Transfected HEK293 Cells-To determine whether effects of mutations Y1236F, T1241A, Y1243F, and N1245A on the drug FIG. 1. Login to comment
140 The only mutation that affected LTC4 transport was conversion of Tyr1243 to Phe, which decreased transport of LTC4 by ϳ30% (Fig. 4). Login to comment
142 However, mutations Y1243F and N1245A both decreased the levels of E217betaG transport ϳ5-6-fold (Fig. 5). Login to comment
144 Kinetic Parameters of [3 H]LTC4 and [3 H]E217betaG Transport-We have shown that mutation Y1243F affected the ability of the protein to transport both LTC4 and E217betaG and that mutation N1245A decreased the transport of only E217betaG. Login to comment
159 However, replacement of Tyr1243 with Phe decreased the normalized Vmax value for LTC4 transport ϳ30% relative to wild type MRP1 (Vmax ϭ 75 pmol/mg/min for mutation Y1243F). Login to comment
160 The apparent Km value for mutation Y1243F was 112 nM (Fig. 6 and Table II). Login to comment
161 Thus, the Y1243F mutation decreased the Vmax/Km ratio for LTC4 ϳ2-fold. Login to comment
162 For E217betaG transport, a nonlinear regression analysis of the data generated a Km value of 1.4 ␮M for wild type MRP1, consistent with previous estimates (10), compared with 5.4 and 10.9 ␮M for mutations Y1243F and N1245A, respectively (Fig. 6 and Table II). Login to comment
163 The normalized Vmax values for mutations Y1243F and N1245A were lower than that for wild type MRP1 (Vmax ϭ 403 pmol/mg/min for wild type MRP1 versus 316 pmol/ mg/min for mutation Y1243F and 288 pmol/mg/min for mutation N1245A) (Fig. 6 and Table II). Login to comment
164 Thus mutations Y1243F and N1245A decreased the Vmax/Km ratio for E217betaG ϳ5-and 11-fold, respectively. Login to comment
165 Effect of Mutations Y1243F and N1245A on the Inhibition of MRP1-mediated E217betaG/LTC4 Transport by LTC4/ E217betaG-As an alternative means of assessing the effects of the TM17 mutations on the interaction between LTC4 and the human protein, we examined the ability of LTC4 to inhibit transport of E217betaG. Login to comment
168 Converting Asn1245 to Ala reproducibly decreased the IC50 value (207 nM), whereas mutation of Tyr1243 to Phe resulted in a slight, reproducible increase (407 nM). Login to comment
170 For the wild type protein, the IC50 value for E217betaG was 3.6 ␮M compared with 11.8 ␮M for mutation Y1243F and 15.1 ␮M for mutation N1245A. Login to comment
171 Since these results are independent of protein expression levels, they provide additional evidence that the observed decrease in transport of mutations Y1243F and N1245A at nonsaturating concentrations of E217betaG is primarily attributable to changes in the affinity of the proteins for this substrate. Login to comment

PMID: 16105987 [PubMed] Wu P et al: "Analysis of human multidrug resistance protein 1 (ABCC1) by matrix-assisted laser desorption ionization/time of flight mass spectrometry: toward identification of leukotriene C4 binding sites."

No. Sentence Comment

262 Likewise, substitution of Tyr1243 with Phe causes a 70% reduction in 17beta-estradiol-D-17beta-glucuronide transport but has little effect on LTC4 transport (Zhang et al., 2002). Login to comment

PMID: 16442101 [PubMed] Frelet A et al: "Insight in eukaryotic ABC transporter function by mutation analysis."

No. Sentence Comment

474 Other mutations either affected the transport of LTC4 and/or E217G (Y1243F) or reduced resistance to drugs (Y1236F, T1241A and Y1243F), suggesting that residues of the cytoplasmic half of TM17 with side chain hydrogen bonding potential participate in the formation of a substrate-binding site [218]. Login to comment

PMID: 17295059 [PubMed] Chang XB et al: "A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1."

No. Sentence Comment

117 Many mutations in TM17, such as Y1236F, T1241A, T1242A, T1242C, T1242S, T1242L, Y1243F, N1245A, W1246C, W1246A, W1246F, W1246Y, or R1249K, significantly affect MRP1 function [83-86]. Login to comment

PMID: 19949927 [PubMed] Chang XB et al: "Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1."

No. Sentence Comment

104 Mutations of C43S in TM1 (112); P343A, K332L and K332D in TM6 (113, 114); W445A and P448A in TM8 (113, 115); T550A, T556A and P557A in TM10 (113, 116); N590A, F594A, P595A, N597A, S604A and S605A in TM11 (113, 117, 118); E1089Q, E1089A, E1089L, E1089N, K1092, S1097 and N1100 in TM14 (119, 120); R1197K in TM16 (121); Y1236F, T1241A, T1242A, T1242C, T1242S, T1242L, Y1243F, N1245A, W1246C, W1246A, W1246F, W1246Y or R1249K in TM17 (121-124) significantly affect MRP1 function. Login to comment