ABCB1 p.Ser228Thr
| Predicted by SNAP2: | A: N (78%), C: N (61%), D: D (71%), E: D (75%), F: D (71%), G: N (82%), H: D (71%), I: N (53%), K: D (80%), L: D (59%), M: D (63%), N: D (53%), P: N (53%), Q: D (66%), R: D (80%), T: N (78%), V: N (57%), W: D (71%), Y: D (75%), |
| 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: N, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D, |
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[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.
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No. Sentence Comment
301 Cell linea Drugb Mutation VINC DNR DEX PURO COLC ACT D MSPP-1 (1) NCc 2 222 2 ϩϩϩ NC W231L MSPP-7 (2) NC 22 222 22 ϩϩϩϩ NC W231L MSPP-55 (3) NC 2 222 22 ϩϩϩ NC W231L MSPP-6 (2) ϩ NC 222 22 22 NC H346N MSPP-17 (2) 2 22 222 22 22 NC A301T MSPP-4 (2) NC NC 222 2 2 NC A301V MSPP-35 (3) NC NC 222 NC 2 NC A301V MSPP-21 (2) 2 22 222 2 2 NC S228T a The numbers within the parentheses refer to the selection experiment in which the variant was isolated.
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ABCB1 p.Ser228Thr 10400654:301:401
status: NEW[hide] Evidence for the locations of distinct steroid and... Mol Pharmacol. 2002 Nov;62(5):1238-48. Gruol DJ, King MN, Kuehne ME
Evidence for the locations of distinct steroid and Vinca alkaloid interaction domains within the murine mdr1b P-glycoprotein.
Mol Pharmacol. 2002 Nov;62(5):1238-48., [PMID:12391288]
Abstract [show]
P-glycoproteins (P-gp) cause the efflux of a wide variety of unrelated hydrophobic compounds out of cells. However, the locations of the sites at which different classes of molecules initially interact with the protein are not well defined. A unique system was developed to search for P-gp drug-interaction domains using mutational analysis. The strategy is based upon identifying mutations that cause a decrease in the activity of P-gp inhibitors, which are structurally related to chemotherapeutic drugs transported by P-gps. Evidence of distinct steroid and taxane interaction domains has already been presented. The work reported here extends the study of the steroid interaction domain and presents evidence for a separate vinblastine interaction domain. A total of 10 steroid-related mutations, involving seven amino acids that are confined within transmembrane segments (TMS) 4 to 6, have been characterized. The location of these mutations indicates that steroids interact with the transporter within the inner leaflet of the plasma membrane. Four previously unidentified, Vinca-related mutations, involving three amino acids, have also been found. Unexpectedly, these mutations are clustered within an eight-amino acid segment proximal to the TMS-4 region. This portion of the protein is thought to be within the cytoplasmic compartment of the cell. Thus, the results suggest that at least part of the initial interaction between P-gp and Vinca alkaloids occurs in the cytoplasm. The steroid interaction domain does not extend into this region of the protein. However, this cytoplasmic section of the protein is likely to play an important role in promoting steroid transport.
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No. Sentence Comment
179 The most pronounced effect was caused by the S228T mutation expressed in the MSPP-21 cells.
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ABCB1 p.Ser228Thr 12391288:179:45
status: NEW