ABCB1 p.Phe335Ser
| Predicted by SNAP2: | A: D (71%), C: D (63%), D: D (85%), E: D (85%), G: D (75%), H: D (85%), I: D (63%), K: D (91%), L: D (66%), M: N (53%), N: D (75%), P: D (91%), Q: D (80%), R: D (91%), S: D (75%), T: D (80%), V: D (66%), W: D (75%), Y: D (71%), |
| 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: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Identification of P-glycoprotein mutations causing... J Biol Chem. 1999 Jul 16;274(29):20318-27. Vo QD, Gruol DJ
Identification of P-glycoprotein mutations causing a loss of steroid recognition and transport.
J Biol Chem. 1999 Jul 16;274(29):20318-27., 1999-07-16 [PMID:10400654]
Abstract [show]
P-glycoproteins transport a wide variety of hydrophobic compounds out of cells. While the diversity of transported molecules suggests a mechanism involving broad specificity, there is evidence of significant discrimination within given classes of molecules. One example of this behavior is transport of corticosteroids by the murine mdr1 P-glycoprotein. The presence of hydroxyl groups, associated with specific steroid carbon atoms, regulates the ability of corticosteroids to be transported. This specificity is demonstrated here by experiments measuring the ability of steroids to inhibit drug transport. The results indicate that a keto oxygen associated with the 3- and 20-carbon atoms, as well as a 17-carbon hydroxyl group, each acts to enhance steroidal P-glycoprotein inhibitory activity. Moreover, inhibitory steroids can be used for directed selection of variant cells, expressing mutated P-glycoproteins with a severely impaired ability to transport dexamethasone. The five mutations, reported here, are located within transmembrane domains 4-6, proximal to the cytoplasmic interface. The altered P-glycoproteins exhibit reduced capacity to be inhibited by specific steroids, suggesting decreased capacity to bind these molecules avidly. Studies comparing the relative inhibitory activity of a series of steroids indicate that these mutations alter recognition of the 17alpha-hydroxyl group and the 20-keto oxygen atom.
Comments [show]
None has been submitted yet.
No. Sentence Comment
310 A F335A or F335S change caused increased resistance to doxorubicin.
X
ABCB1 p.Phe335Ser 10400654:310:11
status: NEW[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
120 To test theeffects of other changes to these two residues, site-directed mutagenesis was used to change either Phe-335 or Phe-978 to serine (polar residue), leucine (small non-polar residue),or to tyrosine (aromatic residue withpolar side chain).
X
ABCB1 p.Phe335Ser 8104183:120:111
status: NEW135 A vinblastine/colchicine ratio of 4.1 was obtained for the wild-type enzyme, whereas mutants Phe335 to Ala or Ser hadvalues of 0.59and 0.44respectively.
X
ABCB1 p.Phe335Ser 8104183:135:93
status: NEW243 It has been found that mutations of Pro-223 toAla, Pro-866 toAla (Loo and Clarke, 1993), Phe-978 toAla or Ser (this study), and Ser-941 to Phe (Groset al., 1991) yield proteins that have reduced ability to conferresistanceto colchicine butretainthecapacity to conferresistancetovinblastine.The oppositeeffect is observed for mutation of Phe-335 to Ala or Ser (this study) or Gly-185 to Val (Choi et al., 1988).
X
ABCB1 p.Phe335Ser 8104183:243:337
status: NEW