ABCB1 p.Phe978Leu
| Predicted by SNAP2: | A: D (66%), C: N (57%), D: D (91%), E: D (85%), G: D (80%), H: D (80%), I: N (78%), K: D (85%), L: N (66%), M: N (53%), N: D (75%), P: D (91%), Q: D (71%), R: D (85%), S: N (53%), T: D (71%), V: N (61%), W: D (85%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: 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, W: D, Y: N, |
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[hide] Functional consequences of phenylalanine mutations... J Biol Chem. 1993 Sep 25;268(27):19965-72. Loo TW, Clarke DM
Functional consequences of phenylalanine mutations in the predicted transmembrane domain of P-glycoprotein.
J Biol Chem. 1993 Sep 25;268(27):19965-72., 1993-09-25 [PMID:8104183]
Abstract [show]
Site-directed mutagenesis was used to investigate whether phenylalanine residues in predicted transmembrane sequences play essential roles in the function of human P-glycoprotein. Mutant cDNAs, in which codons for each of the 31 phenylalanine residues were changed to alanine, were expressed in mouse NIH 3T3 cells and analyzed with respect to their ability to confer resistance to various drugs. Mutation of either Phe-335 to Ala in transmembrane segment 6, or Phe-978 to Ala in transmembrane segment 12, drastically altered the drug resistance profile conferred by the mutant P-glycoprotein in transfected cells. Mutant Phe-335-->Ala conferred little resistance to vinblastine or actinomycin D but retained the ability to confer resistance to colchicine and adriamycin. The mutant also showed increased binding of azidopine, which could be inhibited by lower levels of vinblastine, relative to the wild-type enzyme. By contrast, mutant Phe-978-->Ala conferred little or no resistance to colchicine or adriamycin, while its ability to confer resistance to vinblastine or actinomycin D was retained. These results suggest that Phe-335 and Phe-978 play important roles in the recognition and transport of specific substrates by P-glycoprotein. Mutation of Phe-777 to Ala affected the biosynthesis of the transporter. Mutation of the other 28 phenylalanine residues yielded protein products with structural and functional characteristics that were indistinguishable from the wild-type enzyme.
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No. Sentence Comment
126 Mutants with changes of Phe-978 to Ser, Leu, or Tyr all retained the ability to confer resistance to vinblastine, since drug-resistantcolonies were obtained after transfection with the corresponding mutant cDNAs.
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ABCB1 p.Phe978Leu 8104183:126:24
status: NEW166 Substitution of Phe-978 with Leu had an intermediate effect; drug transport was impaired for all four drugs with the greatest reduction occurring in the presence of colchicine and adriamycin.
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ABCB1 p.Phe978Leu 8104183:166:16
status: NEW[hide] New light on multidrug binding by an ATP-binding-c... Trends Pharmacol Sci. 2006 Apr;27(4):195-203. Epub 2006 Mar 20. Shilling RA, Venter H, Velamakanni S, Bapna A, Woebking B, Shahi S, van Veen HW
New light on multidrug binding by an ATP-binding-cassette transporter.
Trends Pharmacol Sci. 2006 Apr;27(4):195-203. Epub 2006 Mar 20., [PMID:16545467]
Abstract [show]
ATP-binding-cassette (ABC) multidrug transporters confer multidrug resistance to pathogenic microorganisms and human tumour cells by mediating the extrusion of structurally unrelated chemotherapeutic drugs from the cell. The molecular basis by which ABC multidrug transporters bind and transport drugs is far from clear. Genetic analyses during the past 14 years reveal that the replacement of many individual amino acids in mammalian multidrug resistance P-glycoproteins can affect cellular resistance to drugs, but these studies have failed to identify specific regions in the primary amino acid sequence that are part of a defined drug-binding pocket. The recent publication of an X-ray crystallographic structure of the bacterial P-glycoprotein homologue MsbA and an MsbA-based homology model of human P-glycoprotein creates an opportunity to compare the original mutagenesis data with the three-dimensional structures of transporters. Our comparisons reveal that mutations that alter specificity are present in three-dimensional 'hotspot' regions in the membrane domains of P-glycoprotein.
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No. Sentence Comment
62 Another replacement in this cluster in TMH12 (F978L) reduces resistance to colchicine and daunomycin but has no significant effect on the resistance to vinblastine and actinomycin D [16].
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ABCB1 p.Phe978Leu 16545467:62:46
status: NEW60 Another replacement in this cluster in TMH12 (F978L) reduces resistance to colchicine and daunomycin but has no significant effect on the resistance to vinblastine and actinomycin D [16].
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ABCB1 p.Phe978Leu 16545467:60:46
status: NEW