ABCC11 p.Gln1086Glu
| Predicted by SNAP2: | A: D (71%), C: D (71%), D: D (75%), E: D (80%), F: D (80%), G: D (66%), H: D (80%), I: D (80%), K: D (85%), L: D (80%), M: D (66%), N: D (63%), P: D (91%), R: D (85%), S: D (63%), T: D (66%), V: D (75%), W: D (85%), Y: D (80%), |
| 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, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Photolabeling of human and murine multidrug resist... J Biol Chem. 2002 Sep 20;277(38):35225-31. Epub 2002 Jul 22. Qian YM, Grant CE, Westlake CJ, Zhang DW, Lander PA, Shepard RL, Dantzig AH, Cole SP, Deeley RG
Photolabeling of human and murine multidrug resistance protein 1 with the high affinity inhibitor [125I]LY475776 and azidophenacyl-[35S]glutathione.
J Biol Chem. 2002 Sep 20;277(38):35225-31. Epub 2002 Jul 22., 2002-09-20 [PMID:12138119]
Abstract [show]
Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent transporter of structurally diverse organic anion conjugates. The protein also actively transports a number of non-conjugated chemotherapeutic drugs and certain anionic conjugates by a presently poorly understood GSH-dependent mechanism. LY475776is a newly developed (125)I-labeled azido tricyclic isoxazole that binds toMRP1 with high affinity and specificity in a GSH-dependent manner. The compound has also been shown to photolabel a site in the COOH-proximal region of MRP1's third membrane spanning domain (MSD). It is presently not known where GSH interacts with the protein. Here, we demonstrate that the photactivateable GSH derivative azidophenacyl-GSH can substitute functionally for GSH in supporting the photolabeling of MRP1 by LY475776 and the transport of another GSH-dependent substrate, estrone 3-sulfate. In contrast to LY475776, azidophenacyl-[(35)S] photolabels both halves of the protein. Photolabeling of the COOH-proximal site can be markedly stimulated by low concentrations of estrone 3-sulfate, suggestive of cooperativity between the binding of these two compounds. We show that photolabeling of the COOH-proximal site by LY475776 and the labeling of both NH(2)- and COOH- proximal sites by azidophenacyl-GSH requires the cytoplasmic linker (CL3) region connecting the first and second MSDs of the protein, but not the first MSD itself. Although required for binding, CL3 is not photolabeled by azidophenacyl-GSH. Finally, we identify non-conserved amino acids in the third MSD that contribute to the high affinity with which LY475776 binds to MRP1.
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No. Sentence Comment
159 The extent of [125 I]LY475776 labeling of E1089Q MRP1 was decreased severalfold relative to that of wild type protein, whereas [125 I]LY475776 labeling of Q1086E mrp1 was slightly enhanced when compared with wild type mrp1 (Fig. 6A, left panel).
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ABCC11 p.Gln1086Glu 12138119:159:155
status: NEW