ABCC1 p.Ser1235Ala
| Predicted by SNAP2: | A: D (53%), C: D (66%), D: D (80%), E: D (85%), F: D (80%), G: D (66%), H: D (80%), I: D (75%), K: D (85%), L: D (75%), M: D (71%), N: D (66%), P: D (80%), Q: D (63%), R: D (80%), T: N (78%), V: D (66%), W: D (85%), Y: D (80%), |
| 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: N, V: D, W: D, Y: D, |
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[hide] Determinants of the substrate specificity of multi... J Biol Chem. 2002 Jun 7;277(23):20934-41. Epub 2002 Mar 29. Zhang DW, Cole SP, Deeley RG
Determinants of the substrate specificity of multidrug resistance protein 1: role of amino acid residues with hydrogen bonding potential in predicted transmembrane helix 17.
J Biol Chem. 2002 Jun 7;277(23):20934-41. Epub 2002 Mar 29., 2002-06-07 [PMID:11925441]
Abstract [show]
Human multidrug resistance protein 1 (MRP1) confers resistance to many natural product chemotherapeutic agents and actively transports structurally diverse organic anion conjugates. We previously demonstrated that two hydrogen-bonding amino acid residues in the predicted transmembrane 17 (TM17) of MRP1, Thr(1242) and Trp(1246), were important for drug resistance and 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG) transport. To determine whether other residues with hydrogen bonding potential within TM17 influence substrate specificity, we replaced Ser(1233), Ser(1235), Ser(1237), Gln(1239), Thr(1241), and Asn(1245) with Ala and Tyr(1236) and Tyr(1243) with Phe. Mutations S1233A, S1235A, S1237A, and Q1239A had no effect on any substrate tested. In contrast, mutations Y1236F and T1241A decreased resistance to vincristine but not to VP-16, doxorubicin, and epirubicin. Mutation Y1243F reduced resistance to all drugs tested by 2-3-fold. Replacement of Asn(1245) with Ala also decreased resistance to VP-16, doxorubicin, and epirubicin but increased resistance to vincristine. This mutation also decreased E(2)17betaG transport approximately 5-fold. Only mutation Y1243F altered the ability of MRP1 to transport both leukotriene 4 and E(2)17betaG. Together with our previous results, these findings suggest that residues with side chain hydrogen bonding potential, clustered in the cytoplasmic half of TM17, participate in the formation of a substrate binding site.
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No. Sentence Comment
3 Mutations S1233A, S1235A, S1237A, and Q1239A had no effect on any substrate tested.
X
ABCC1 p.Ser1235Ala 11925441:3:18
status: NEW112 Substitution of four hydrophilic amino acid residues within TM17 with Ala (S1233A, S1235A, S1237A, Q1239A) had no significant effect on the ability of MRP1 to confer resistance to any drug tested.
X
ABCC1 p.Ser1235Ala 11925441:112:83
status: NEW141 ATP-dependent transport of [3 H]E217betaG was also examined (Fig. 5), but none of the mutations S1233A, S1235A, Y1236F, S1237A, Q1239A, and T1241A had any effect.
X
ABCC1 p.Ser1235Ala 11925441:141:104
status: NEW199 With the exception of Tyr1236 , mutation of the amino acids with polar substituents predicted to be most distant from the membrane/cytoplasm interface (S1233A, S1235A, S1237A, and Q1239A) to Ala had no effect on the ability of MRP1 to confer resistance to any of the drugs tested.
X
ABCC1 p.Ser1235Ala 11925441:199:160
status: NEW