ABCB1 p.Ser222Thr
| Predicted by SNAP2: | A: N (72%), C: N (72%), D: D (53%), E: D (59%), F: D (53%), G: N (57%), H: D (53%), I: N (53%), K: D (63%), L: D (59%), M: N (61%), N: N (61%), P: D (66%), Q: D (59%), R: D (63%), T: N (93%), V: N (57%), W: D (71%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, 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, T: D, V: D, W: D, Y: D, |
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[hide] The use of a novel taxane-based P-glycoprotein inh... Mol Pharmacol. 2001 Jul;60(1):104-13. Gruol DJ, Bernd J, Phippard AE, Ojima I, Bernacki RJ
The use of a novel taxane-based P-glycoprotein inhibitor to identify mutations that alter the interaction of the protein with paclitaxel.
Mol Pharmacol. 2001 Jul;60(1):104-13., [PMID:11408605]
Abstract [show]
Murine thymoma cell lines expressing mutated forms of the mdr1b P-glycoprotein were isolated using a novel taxane-based P-glycoprotein inhibitor tRA-96023 (SB-RA-31012). The selection strategy required resistance to a combination of tRA-96023 and colchicine. Five mutations were identified (N350I, I862F, L865F, L868W, and A933T) that reduce the capacity of tRA-96023 to inhibit P-glycoprotein-dependent drug resistance. These mutations also result in a loss of paclitaxel resistance ranging from 47 to 100%. Four mutations are located in the second half of the protein, within or near the proposed transmembrane segment (TMS) 10--11 regions. The fifth mutation (N350I) is within the first half of the protein, proximal (cytoplasmic) to TMS 6. The variant cell line expressing the L868W mutation was subjected to a second round of selection involving tRA-96023 and the toxic drug puromycin. This resulted in the isolation of a cell line expressing a P-glycoprotein with a double mutation. The additional mutation (N988D) is located within TMS 12 and conveys further decreases in resistance to paclitaxel and the capacity of tRA-96023 to inhibit drug resistance. Taken together, the results indicate a significant contribution by the TMS 10--12 portion of the protein to the recognition and transport of taxanes and give evidence that the cytoplasmic region proximal to TMS 6 also plays a role in taxane interactions with P-glycoproteins. Interestingly, mutations within TMS 6 and 12 were found to cause a partial loss of PSC-833 inhibitor activity, suggesting that these regions participate in the interactions with cyclosporin and its derivatives.
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No. Sentence Comment
219 Of the five mutations reported by Vo and Gruol to affect steroid-Pgp interactions, only one (S222T) causes a TABLE 3 Percentage loss in paclitaxel resistance for the variant cell lines listed in Table 2 A portion of the data that was used to generate Table 2 was converted from fractional loss to percentage loss of paclitaxel resistance.
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ABCB1 p.Ser222Thr 11408605:219:93
status: NEW225 Loss of paclitaxel resistance in this case, however, may be part of a pleiotropic phenomenon, because resistance to all six of the drugs tested were decreased in cells expressing the S222T mutation.
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ABCB1 p.Ser222Thr 11408605:225:183
status: NEW