ABCMdb

ABCB1 p.Ala229Val

Predicted by SNAP2:	C: D (63%), D: D (80%), E: D (80%), F: D (71%), G: N (82%), H: D (75%), I: D (59%), K: D (80%), L: D (71%), M: N (53%), N: D (63%), P: D (80%), Q: D (66%), R: D (75%), S: N (78%), T: N (53%), V: N (66%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	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, S: N, T: D, V: D, W: D, Y: D,

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Publications
[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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Sentences [show]
No. Sentence Comment
119 It contains two closely spaced mutations, A229V and W231L. Login to comment
127 In total, the process identified five new mutations, two of which (A229V, S308L) involve amino acids that had not been previously identified as contributing to steroid interactions with the P-gp. Login to comment
131 The percentage of normalized change in resistance (N.C.R) is defined by the equation: N.C.R ϭ 100% ϫ (VAR IC50 - MS23IC50 )/(MS23 IC50 - W7TB IC50) Cell Line Vincristine Daunomycin Dexamethasone Puromycin Colchicine Mutation MSPD-10 N.C. ` ``` `` `` W231C MSPT-7 `` ``` ``` ``` ` A229V, W231L MSPD-60 `` N.C. ``` `` `` A301D MSMP-1 ` `` `` `` ``` S308L MSAC-52 ` N.C. `` N.C. ϩϩϩϩ L338F N.C., no change; ϩϩϩϩ, NCR increase Ն200%; `, NCR decrease Ն33%; ``, Ն67%; ```, Ն100%. Login to comment