ABCMdb

ABCB1 p.Thr318Ser

Predicted by SNAP2:	A: N (61%), C: D (71%), D: D (75%), E: D (80%), F: D (80%), G: D (59%), H: D (63%), I: N (57%), K: D (85%), L: D (80%), M: D (71%), N: D (59%), P: D (66%), Q: D (75%), R: D (85%), S: N (97%), V: N (61%), W: D (85%), 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: D, P: D, Q: D, R: D, S: N, V: D, W: D, Y: D,

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Publications
[hide] The extracellular loop between TM5 and TM6 of P-gl... Arch Biochem Biophys. 1999 Jul 1;367(1):74-80. Zhou Y, Gottesman MM, Pastan I
The extracellular loop between TM5 and TM6 of P-glycoprotein is required for reactivity with monoclonal antibody UIC2.
Arch Biochem Biophys. 1999 Jul 1;367(1):74-80., [PMID:10375401]

Abstract [show]
P-glycoprotein (P-gp), encoded by the MDR1 gene, is a plasma membrane transporter which confers resistance to many chemotherapeutic drugs. Monoclonal antibodies raised against P-gp have been used as tools to study P-gp topology and activity. Monoclonal antibody UIC2 recognizes a functional conformation of P-gp on the cell surface and blocks P-gp-mediated drug transport. Knowledge about the UIC2 epitope and the mechanism of its inhibitory effects may be helpful for understanding P-gp structure and developing P-gp inhibitors. In the present work, using several chimeras of MDR1 and MDR2, we found that the native sequence of the predicted extracellular loop between transmembrane domains (TM) 5 and 6 of P-gp is necessary, but not sufficient, for UIC2 reactivity. In addition, UIC2 reactivity is also affected by mutations in TM6, a region known to be involved in interactions of P-gp with substrates. These observations suggest that residues in the extracellular loop between TM5 and TM6 are directly involved in the display of the UIC2 epitope. Since TM6 has been shown to be actively involved in drug transport process, the proximity of this region to TM6 may help to explain why UIC2 binding is sensitive to the functional state of P-gp and why binding of UIC2 inhibits P-gp-mediated drug transport.

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No. Sentence Comment
66 Those substitutions are T318S, L322I, G324K, S327T, Q330N, V331A, and L332M (Fig. 1). Login to comment
107 DISCUSSION The Extracellular Loop between TM5 and TM6 Is Essential for UIC2 Recognition In this work, we found that a quadruple substitution of MDR2 residues (T318S, L322I, G324K, and S327T) in the extracellular loop between TM5 and TM6 abolished UIC2 recognition of P-gp. Login to comment
115 Since the substitutions T318S, L322I, G324K, and S327T had little effect on either MRK-16 labeling or multidrug transporter activity, it is less likely that these mutations produce any major changes in P-gp structure. Login to comment
106 DISCUSSION The Extracellular Loop between TM5 and TM6 Is Essential for UIC2 Recognition In this work, we found that a quadruple substitution of MDR2 residues (T318S, L322I, G324K, and S327T) in the extracellular loop between TM5 and TM6 abolished UIC2 recognition of P-gp. Login to comment
114 Since the substitutions T318S, L322I, G324K, and S327T had little effect on either MRK-16 labeling or multidrug transporter activity, it is less likely that these mutations produce any major changes in P-gp structure. Login to comment