ABCC1 p.Trp222Leu
| Predicted by SNAP2: | A: N (57%), C: N (66%), D: D (71%), E: D (59%), F: N (72%), G: D (53%), H: N (61%), I: D (53%), K: D (71%), L: N (61%), M: N (57%), N: N (53%), P: D (75%), Q: N (53%), R: D (66%), S: N (66%), T: N (53%), V: N (53%), Y: N (72%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, Y: D, |
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[hide] MRP1 mutated in the L0 region transports SN-38 but... Biochem Pharmacol. 2005 Oct 1;70(7):1056-65. Noguchi T, Ren XQ, Aoki S, Igarashi Y, Che XF, Nakajima Y, Takahashi H, Mitsuo R, Tsujikawa K, Sumizawa T, Haraguchi M, Kobayashi M, Goto S, Kanehisa M, Aikou T, Akiyama S, Furukawa T
MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (beta-D-glucuronate).
Biochem Pharmacol. 2005 Oct 1;70(7):1056-65., 2005-10-01 [PMID:16098482]
Abstract [show]
Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette transporter that confers multidrug resistance on tumor cells. Much convincing evidence has accumulated that MRP1 transports most substances in a GSH-dependent manner. On the other hand, several reports have revealed that MRP1 can transport some substrates independently of GSH; however, the importance of GSH-independent transport activity is not well established and the mechanistic differences between GSH-dependent and -independent transport by MRP1 are unclear. We previously demonstrated that the amino acids W261 and K267 in the L0 region of MRP1 were important for leukotriene C4 (LTC4) transport activity of MRP1 and for GSH-dependent photolabeling of MRP1 with azidophenyl agosterol-A (azidoAG-A). In this paper, we further tested the effect of W222L, W223L and R230A mutations in MRP1, designated dmL0MRP1, on MRP1 transport activity. SN-38 is an active metabolic form of CPT-11 that is one of the most promising anti-cancer drugs. Membrane vesicles prepared from cells expressing dmL0MRP1 could transport SN-38, but not LTC4 or estradiol-17 (beta-D-glucuronate), and could not be photolabeled with azidoAG-A. These data suggested that SN-38 was transported by a different mechanism than that of GSH-dependent transport. Understanding the GSH-independent transport mechanism of MRP1, and identification of drugs that are transported by this mechanism, will be critical for combating MRP1-mediated drug resistance. We performed a pairwise comparison of compounds that are transported by MRP1 in a GSH-dependent or -independent manner. These data indicated that it may be possible to predict compounds that are transported by MRP1 in a GSH-independent manner.
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No. Sentence Comment
4 In this paper, we further tested the effect of W222L, W223L and R230A mutations in MRP1, designated dmL0MRP1, on MRP1 transport activity.
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ABCC1 p.Trp222Leu 16098482:4:47
status: NEW61 The extra mutations created, W222L, W223L and R230A, were located within WxxxxxK sequences in the L0 region that have been reported to an interacting site of glutathione-S-transferase with GSH.
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ABCC1 p.Trp222Leu 16098482:61:29
status: NEW64 W222L, W223L and R230A mutations were then introduced into this construct by PCR using the forward primers, 50 -GGGTTGATTGTCGCGGGCTACCGCC-30 , and reverse primer 50 -TGTGATCAACAAGAAGGTGATCC- TC-30 (bold denotes mismatched bases encoding the mutation).
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ABCC1 p.Trp222Leu 16098482:64:0
status: NEW136 As described in Section 2, the new mutant MRP1, named dmL0MRP1, was designed to carry the extra mutations, W222L, W223L and R230A, in addition to the previous mutants, W261A and K267M, in L0 region, and the original TMD0 region, in order to avoid the influence of deletion of the TMD0 region (Fig. 1).
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ABCC1 p.Trp222Leu 16098482:136:107
status: NEW[hide] Portrait of multifaceted transporter, the multidru... Pflugers Arch. 2007 Feb;453(5):621-41. Epub 2006 Dec 23. Bakos E, Homolya L
Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1).
Pflugers Arch. 2007 Feb;453(5):621-41. Epub 2006 Dec 23., [PMID:17187268]
Abstract [show]
MRP1 (ABCC1) is a peculiar member of the ABC transporter superfamily for several aspects. This protein has an unusually broad substrate specificity and is capable of transporting not only a wide variety of neutral hydrophobic compounds, like the MDR1/P-glycoprotein, but also facilitating the extrusion of numerous glutathione, glucuronate, and sulfate conjugates. The transport mechanism of MRP1 is also complex; a composite substrate-binding site permits both cooperativity and competition between various substrates. This versatility and the ubiquitous tissue distribution make this transporter suitable for contributing to various physiological functions, including defense against xenobiotics and endogenous toxic metabolites, leukotriene-mediated inflammatory responses, as well as protection from the toxic effect of oxidative stress. In this paper, we give an overview of the considerable amount of knowledge which has accumulated since the discovery of MRP1 in 1992. We place special emphasis on the structural features essential for function, our recent understanding of the transport mechanism, and the numerous assignments of this transporter.
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97 Typical substrates, which are transported as glutathione or glucuronide conjugates, e.g., LTC4 or E217βG, are not transported by an MRP1 variant mutated in the L0 region (W222L, W223L, R231A, W261A, K267M).
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ABCC1 p.Trp222Leu 17187268:97:177
status: NEW[hide] Structural and functional properties of human mult... Curr Med Chem. 2011;18(3):439-81. 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., [PMID:21143116]
Abstract [show]
Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.
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No. Sentence Comment
720 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].
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ABCC1 p.Trp222Leu 21143116:720:71
status: NEW