ABCMdb

PMID: 16816140

Deeley RG, Westlake C, Cole SP
Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins.
Physiol Rev. 2006 Jul;86(3):849-99., [PubMed]

Sentences

No. Mutations Sentence Comment

797 ABCC1 p.Trp1246Cys ABCC1 p.Trp1246Ala ABCC1 p.Trp1246Phe ABCC1 p.Trp1246Tyr For example, mutation of Trp1246 to Cys, Ala, Phe, or Tyr eliminated E217betaG and NNAL-O-glucuronide transport, resistance to natural product drugs, and binding of the GSH-dependent inhibitor LY475776, but had little effect or no effect on LTC4 transport (207, 281, 327). Login to comment 798 ABCC1 p.Trp1246Cys ABCC1 p.Trp1246Ala ABCC1 p.Trp1246Phe ABCC1 p.Trp1246Tyr For example, mutation of Trp1246 to Cys, Ala, Phe, or Tyr eliminated E217betaG and NNAL-O-glucuronide transport, resistance to natural product drugs, and binding of the GSH-dependent inhibitor LY475776, but had little effect or no effect on LTC4 transport (207, 281, 327). Login to comment 799 ABCC1 p.Trp1246Cys ABCC1 p.Trp1246Ala ABCC1 p.Trp1246Phe ABCC1 p.Trp1246Tyr For example, mutation of Trp1246 to Cys, Ala, Phe, or Tyr eliminated E217betaG and NNAL-O-glucuronide transport, resistance to natural product drugs, and binding of the GSH-dependent inhibitor LY475776, but had little effect or no effect on LTC4 transport (207, 281, 327). Login to comment 833 ABCC1 p.Glu1204Leu The distinct phenotypes associated with mutations of the highly conserved Arg1202 and Glu1204 are presumably caused by perturbations in the ␣-helical geometry of TM16 that contribute (depending on the substituting amino acid) to misfolding of MRP1 and, in the case of the neutral Glu1204 Leu mutant, disruption of the signaling between the TMs that comprise the substrate translocation pathway through the membrane and NBD2. Login to comment 834 ABCC1 p.Glu1204Leu The distinct phenotypes associated with mutations of the highly conserved Arg1202 and Glu1204 are presumably caused by perturbations in the ␣-helical geometry of TM16 that contribute (depending on the substituting amino acid) to misfolding of MRP1 and, in the case of the neutral Glu1204 Leu mutant, disruption of the signaling between the TMs that comprise the substrate translocation pathway through the membrane and NBD2. Login to comment 835 ABCC1 p.Glu1204Leu The distinct phenotypes associated with mutations of the highly conserved Arg1202 and Glu1204 are presumably caused by perturbations in the ␣-helical geometry of TM16 that contribute (depending on the substituting amino acid) to misfolding of MRP1 and, in the case of the neutral Glu1204 Leu mutant, disruption of the signaling between the TMs that comprise the substrate translocation pathway through the membrane and NBD2. Login to comment 839 ABCC1 p.Tyr1236Phe Despite the complete conservation of this region in MRP1, the only mutation that affected function was the conversion of Tyr1236 to Phe that selectively decreased resistance to vincristine (567) (Fig. 9). Login to comment 840 ABCC1 p.Tyr1236Phe Despite the complete conservation of this region in MRP1, the only mutation that affected function was the conversion of Tyr1236 to Phe that selectively decreased resistance to vincristine (567) (Fig. 9). Login to comment 841 ABCC1 p.Tyr1236Phe Despite the complete conservation of this region in MRP1, the only mutation that affected function was the conversion of Tyr1236 to Phe that selectively decreased resistance to vincristine (567) (Fig. 9). Login to comment 846 ABCC1 p.Phe594Trp ABCC1 p.Phe594Tyr Conservative substitutions of Phe594 with Tyr or Trp had selective effects on substrate specificity, suggesting that it may be involved in direct interaction of MRP1 with its substrates (52). Login to comment 847 ABCC1 p.Phe594Trp ABCC1 p.Phe594Tyr Conservative substitutions of Phe594 with Tyr or Trp had selective effects on substrate specificity, suggesting that it may be involved in direct interaction of MRP1 with its substrates (52). Login to comment 848 ABCC1 p.Phe594Trp ABCC1 p.Phe594Tyr ABCC1 p.Asn590Ala Similarly, only Ala substitution of Asn590 (a "cavity"-creating substitution) adversely affected MRP1 activity, while replacing this residue with Asp or Gln had no effect, suggesting that the polar side chain of Asn590 may be involved in interhelical interactions that influence the conformation of the protein in the vicinity of the binding pocket (570). Login to comment 849 ABCC1 p.Asn590Ala Similarly, only Ala substitution of Asn590 (a "cavity"-creating substitution) adversely affected MRP1 activity, while replacing this residue with Asp or Gln had no effect, suggesting that the polar side chain of Asn590 may be involved in interhelical interactions that influence the conformation of the protein in the vicinity of the binding pocket (570). Login to comment 850 ABCC1 p.Asn590Ala Similarly, only Ala substitution of Asn590 (a "cavity"-creating substitution) adversely affected MRP1 activity, while replacing this residue with Asp or Gln had no effect, suggesting that the polar side chain of Asn590 may be involved in interhelical interactions that influence the conformation of the protein in the vicinity of the binding pocket (570). Login to comment 883 ABCC1 p.Trp445Ala Thus Ala substitution of Trp445 (TM8), Trp553 (TM10), and Trp1198 (TM16) eliminated or dramatically reduced transport levels of a broad range of organic anion substrates. Login to comment 884 ABCC1 p.Trp445Ala Thus Ala substitution of Trp445 (TM8), Trp553 (TM10), and Trp1198 (TM16) eliminated or dramatically reduced transport levels of a broad range of organic anion substrates. Login to comment 885 ABCC1 p.Trp445Ala Thus Ala substitution of Trp445 (TM8), Trp553 (TM10), and Trp1198 (TM16) eliminated or dramatically reduced transport levels of a broad range of organic anion substrates. Login to comment 909 ABCC1 p.Phe594Ala Indeed, mutation of Phe594 to Ala drastically reduced transport of four different substrates tested and eliminated photolabeling by LTC4 (52). Login to comment 910 ABCC1 p.Phe594Ala Indeed, mutation of Phe594 to Ala drastically reduced transport of four different substrates tested and eliminated photolabeling by LTC4 (52). Login to comment 911 ABCC1 p.Phe594Ala Indeed, mutation of Phe594 to Ala drastically reduced transport of four different substrates tested and eliminated photolabeling by LTC4 (52). Login to comment