ABCMdb

ABCB1 p.Val981Ala

Predicted by SNAP2:	A: D (63%), C: D (63%), D: D (91%), E: D (85%), F: D (75%), G: D (85%), H: D (85%), I: N (87%), K: D (91%), L: N (61%), M: N (72%), N: D (85%), P: D (91%), Q: D (85%), R: D (85%), S: D (71%), T: D (66%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D,

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[hide] Biochemical, cellular, and pharmacological aspects... Annu Rev Pharmacol Toxicol. 1999;39:361-98. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM
Biochemical, cellular, and pharmacological aspects of the multidrug transporter.
Annu Rev Pharmacol Toxicol. 1999;39:361-98., [PMID:10331089]

Abstract [show]
Considerable evidence has accumulated indicating that the multidrug transporter or P-glycoprotein plays a role in the development of simultaneous resistance to multiple cytotoxic drugs in cancer cells. In recent years, various approaches such as mutational analyses and biochemical and pharmacological characterization have yielded significant information about the relationship of structure and function of P-glycoprotein. However, there is still considerable controversy about the mechanism of action of this efflux pump and its function in normal cells. This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.

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47 Table 1 List of mutations in human, mouse, and hamster P-glycoproteins that affect substrate specificitya aa mutation Region Sourceb Reference H61R, F, K, M, W, Y TM 1 Human MDR1 149, 150 ABC20c G64R TM 1 Human MDR1 150 L65R TM 1 Human MDR1 150 aa78-97 EC 1 Human MDR1 151 Q128Hd TM 2 Mouse mdr3 152 R138H IC 1 Mouse mdr3 152 Q139H, R IC 1 Mouse mdr3 152 Q141V IC 1 Human MDR1 15319, Q145H IC 1 Mouse mdr3 152 E155G, K IC 1 Mouse mdr3 152 F159I IC 1 Mouse mdr3 152 D174G IC 1 Mouse mdr3 152 S176G, P IC 1 Mouse mdr3 152 K177I IC 1 Mouse mdr3 152 N179S IC 1 Mouse mdr3 152 N183S/G185V IC 1 Human MDR1 154 G183D IC 1 Mouse mdr3 152 G185V IC 1 Human MDR1 155-157 G187V IC 1 Human MDR1 153 A192T TM 3 Mouse mdr3 152 F204S EC 2 Mouse mdr3 152 W208G EC 2 Mouse mdr3 152 K209E EC 2 Mouse mdr3 152 L210I TM 4 Mouse mdr3 152 T211P TM 4 Mouse mdr3 152 I214T TM 4 Mouse mdr3 152 P223A TM 4 Human MDR1 158 G288V IC 2 Human MDR1 153 I299M, T319S, L322I, TM 5, EC3, Human MDR1 159 G324K, S351N IC 3 F335A TM 6 Human MDR1 19 F335 TM 6 Human MDR1 160 V338A TM 6 Human MDR1 161 G338A, A339P TM 6 Hamster PGY1 162, 163 A339P TM 6 Hamster PGY1 163 G341V TM 6 Human MDR1 161 K536R, Q N-NBD Human MDR1 164 ERGA → DKGT N-NBD Mouse mdr3 165 aa 522-525 T578C N-NBD Mouse mdr3 165 (Continued) G830V IC 4 Human MDR1 P866A TM 10 Human MDR1 158 F934A TM 11 Mouse mdr3 166 G935A TM 11 Mouse mdr3 166 I936A TM 11 Mouse mdr3 166 F938A TM 11 Mouse mdr3 166 S939A TM 11 Mouse mdr3 166 S939F TM 11 Mouse mdr3 167, 168 S941F TM 11 Mouse mdr1 167, 168 T941A TM 11 Mouse mdr3 166 Q942A TM 11 Mouse mdr3 166 A943G TM 11 Mouse mdr3 166 Y946A TM 11 Mouse mdr3 166 S948A TM 11 Mouse mdr3 166 Y949A TM 11 Mouse mdr3 166 C952A TM 11 Mouse mdr3 166 F953A TM 11 Mouse mdr3 166 F983A TM 12 Human MDR1 169 L975A, V981A, F983A TM 12 Human MDR1 169 M986A, V988A, Q990A, TM 12 Human MDR1 169 V991A V981A, F983A TM 12 Human MDR1 169 L975A, F983A TM 12 Human MDR1 169 L975A, V981A TM 12 Human MDR1 169 F978A TM 12 Human MDR1 19 a aa,amino acid; EC, extracellular loop; IC, intracellular loop; TM,transmembrane domain; NBD, nucleotide binding/utilization domain. Login to comment

[hide] A single amino acid residue contributes to distinc... Biochemistry. 1999 May 18;38(20):6630-9. Dey S, Hafkemeyer P, Pastan I, Gottesman MM
A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol.
Biochemistry. 1999 May 18;38(20):6630-9., 1999-05-18 [PMID:10350482]

Abstract [show]
Both cis and trans isomers of the dopamine receptor antagonist flupentixol inhibit drug transport and reverse drug resistance mediated by the human multidrug transporter P-glycoprotein (Pgp) with a stereoselective potency. The rate of ATP hydrolysis by Pgp and photoaffinity labeling of Pgp with the substrate analogue [125I]iodoarylazidoprazosin ([125I]IAAP) are modulated by each isomer in an opposite manner, suggesting different mechanisms for the inhibitory effect on drug transport. In this study we demonstrate that substitution of a single phenylalanine residue at position 983 (F983) with alanine (F983A) in putative transmembrane (TM) region 12 selectively affects inhibition of Pgp-mediated drug transport by both isomers of flupentixol. In F983A the stimulatory effect of cis(Z)-flupentixol and the inhibitory effect of trans(E)-flupentixol on ATP hydrolysis and [125I]IAAP labeling were significantly altered. This indicates that F983 contributes to inhibition of drug transport by both isomers of flupentixol and plays an important role in stimulation and inhibition of ATP hydrolysis and [125I]IAAP labeling by cis(Z)- and trans(E)-flupentixol, respectively. The near-wild-type level of drug transport by the F983A Pgp mutant dissociates susceptibility to inhibition by flupentixol from drug translocation, indicating the allosteric nature of the flupentixol interaction. The inhibitory effects of cyclosporin A on drug transport, drug-stimulated ATP hydrolysis, and [125I]IAAP labeling as well as the stimulatory effect of verapamil on ATP hydrolysis by Pgp were minimally affected by substitution of F983, suggesting no global alteration in the structural and functional integrity of the mutant. Taken together, our data suggest that distinct mechanisms of inhibition of Pgp-mediated drug transport by the cis and trans isomers of flupentixol are mediated through a common site of interaction.

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127 In a recent study, seven amino acid residues, L975, V981, F983, M986, V988, Q990, and V991, in the putative TM 12 of human Pgp were substituted individually by alanine (L975A, V981A, F983A, M986A, V988A, Q990A, and V991A). Login to comment
133 Consistent with the previous report, all the mutant Pgp`s (L975A, V981A, F983A, M986A, V988A, Q990A, and V991A) were expressed on the cell surface at a comparable level to that of wild-type (WT) Pgp (Figure 1A, upper panel). Login to comment
141 Human osteosarcoma (HOS) cells infected with vTF7-3 were transfected with either pTM1 (control) (s), pTM1-MDR1 (wild type) (-), pTM1-MDR1-L975A (L975A) (‚‚‚), pTM1-MDR1-V981A (V981A) (- - -), pTM1-MDR1-F983A (F983A) (- -), pTM1-MDR1-M986A (M986A) (thick dashes), pTM1-MDR1-V988A (V988A) (-‚‚-), pTM1-MDR1-Q990A (Q990A) (-‚-), or pTM1-MDR1-V991A (V991A) (-‚‚‚-) plasmid DNA. Login to comment
143 (A, upper panel) Cells were subjected to FACS analysis after staining with human Pgp external epitope-specific monoclonal antibody MRK-16 (14), as described under Experimental Procedures. (A, lower panel) Total cell lysates were prepared from each cell type, and immunoblot analysis with Pgp-specific monoclonal antibody C219 was performed as described under Experimental Procedures. (B) Similar to section A; cells were infected with vTF7-3, and transfected with either pTM1 (control) (s), pTM1-MDR1 (wild type) (-), pTM1-MDR1-L975A (L975A) (‚‚‚), pTM1-MDR1-V981A (V981A) (- - -), pTM1-MDR1-F983A (F983A) (- -), pTM1-MDR1-M986A (M986A) (thick dashes) pTM1-MDR1-V988A (V988A) (-‚‚-), pTM1-MDR1-Q990A (Q990A) (-‚-), or pTM1-MDR1-V991A (V991A) (-‚‚‚-) plasmid DNAs. Login to comment
158 In cells expressing mutants V981A (Figure 2A,B) and M986A (data not shown), the level of intracellular accumulation of Bodipy Fl-verapamil was effectively increased by both isomers of flupentixol, but not to the same extent as that of the cells expressing wild-type Pgp. Login to comment
159 This suggested that inhibition of drug transport by cis(Z)- and trans(E)- flupentixol in V981A and M986A was not complete, indicating a moderate contribution of these residues to the interaction with flupentixol. Login to comment
165 Steady-state accumulation of Bodipy FL-verapamil was measured by FACS in the presence (- - -) and absence (s) of 10 µM cis(Z)-flupentixol (A) or 5 µM trans(E)-flupentixol (B) in HOS cells infected with vTF7-3 and transfected with either pTM1 (pTM1), pTM1-MDR1 (WT), pTM1-MDR1-L975A (L975A), pTM1-MDR1-V981A (V981A), or pTM1-MDR1-F983A (F983A). Login to comment
239 Although drug transport was inhibited by both cis(Z)- and trans(E)-flupentixol in V981A and M986A (data not shown), inhibition was not complete, FIGURE 6: Effect of trans(E)-flupentixol and cyclosporin A on [125I]IAAP labeling of the wild-type Pgp and F983A. Login to comment
246 It is to be noted that in all three mutants (F983A, V981A, and M986A) the inhibitory effect of both isomers (cis and trans) of flupentixol was affected. Login to comment

[hide] Contribution to substrate specificity and transpor... Biochemistry. 1998 Nov 17;37(46):16400-9. Hafkemeyer P, Dey S, Ambudkar SV, Hrycyna CA, Pastan I, Gottesman MM
Contribution to substrate specificity and transport of nonconserved residues in transmembrane domain 12 of human P-glycoprotein.
Biochemistry. 1998 Nov 17;37(46):16400-9., 1998-11-17 [PMID:9819232]

Abstract [show]
P-glycoprotein (Pgp), the product of the MDR1 gene, confers multidrug resistance on cancer cells by ATP-dependent extrusion of anticancer drugs. Biochemical and genetic studies with Pgp have identified the putative transmembrane (TM) region 12 (residues 974-994) as a major region involved in drug interactions with amino acid residues conserved among Pgp family members shown to be essential for transport. To determine whether nonconserved residues might be involved in substrate specificity, seven amino acid residues were identified within TM 12 that were not strictly conserved among the MDR1 and MDR2 family of proteins from different mammalian species. We replaced all seven of these amino acid residues with alanine, one at a time and in combinations, and used a vaccinia virus based transient expression system to analyze function. None of the single replacements caused any alteration in transport function. However, when residues L975, V981, and F983 were replaced collectively, drug transport, drug-stimulated ATP hydrolysis, and photoaffinity labeling with the drug analogue, [125I]iodoarylazidoprazosin (IAAP), were abrogated, with little effect on [alpha-32P]-8-azido-ATP labeling and basal ATPase activity. Pairwise alanine substitutuions showed variable effects on function. Substitutions including L975A in combination with any one of the other two replacements had the least effect on Pgp function. The V981A and F983A double mutant showed the most effect on transport of fluorescent substrates. In contrast, alanine substitutions of all four nonconserved residues M986, V988, Q990, and V991 at the putative carboxy-terminal half of TM 12 showed no effect on drug transport except for a partial reduction in bodipy-verapamil extrusion. These results suggest that nonconserved residues in the putative amino-proximal half of TM 12 of Pgp play a more direct role in determining specificity of drug transport function than those in the putative carboxy-terminal half of TM 12.

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8 The V981A and F983A double mutant showed the most effect on transport of fluorescent substrates. Login to comment
50 Moreover, double mutants based on the triple mutant were cloned (L975A-V981A-F983, L975A-V981-F983A, L975- V981A-F983A). Login to comment
98 Alanine mutants were arranged in such a way that three alanine mutations were putatively located in the outer plasma membrane leaflet (L975A, V981A, and F983A) and four in the inner leaflet (M986A, V988A, Q990A, and V991A), assuming an R-helical structure to TM 12 (Figure 1b). Login to comment
124 Double mutants combining pairwise L975A, V981A, and F983A were constructed in order to determine the critical nonconserved residues that were responsible for mediating drug transport in the amino-proximal half of TM 12. Login to comment
125 Those double mutants were L975A-V981A, L975A-F983A, and V981A-F983A. Login to comment
126 The V981-F983 double mutant was Table 1: Properties of Wild-Type and Mutant P-glycoproteinsa drug transporta cell surface expressionc rhodamine daunomycin bodipy-verapamil calcein-AM bodipy-taxol wild-type ++++ ++++ ++++ ++++ ++++ ++++ L975A ++++ ++++ ++++ ++++ ++++ ++++ V981A ++++ ++++ ++++ ++++ ++++ ++++ F983A ++++ ++++ ++++ ++++ ++++ ++++ M986A ++++ ++++ n.d. ++++ ++++ n.d. V988A ++++ ++++ n.d. ++++ ++++ n.d. Q990A ++++ ++++ n.d. ++++ ++++ n.d. V991A ++++ ++++ n.d. ++++ ++++ n.d. L975A, V981A, F983A ++++ no transport no transport ++ ++ ++ M986A, V988A, Q990A, V991A ++++ ++++ +++ ++ ++++ ++++ V981A, F983A ++++ + no transport ++ ++ +++ L975A, F983A ++++ + ++ ++++ +++ ++++ L975A, V981A ++++ ++ no transport ++++ +++ ++++ a Symbols are noted as follows: ++++, wild-type activity; ++, impaired activity; +, residual activity; and n.d., not determined. b Drug transport was determined by FACS. Login to comment
130 Mutant Pgp`s are the triple mutant in the amino-proximal half of TM 12 (L975A-V981A-F983A, - -), the quadruple mutant in the carboxy-terminal half of TM 12 (M986A-V988A-Q990A-V991A, ‚‚‚), the double mutants L975A-V981A (- - -), L975A-F983A (-‚‚-), and V981A-F983A (-‚-). Login to comment
134 The double mutants involving L975A and either V981A and/or F983A were still capable of transporting calcein-AM, bodipy-taxol, and bodipy-verapamil but rhodamine 123 and daunorubicin transport was significantly reduced compared to wild-type Pgp (Figure 4), indicating a significant contribution of L975 to drug specificity. Login to comment
141 Mutant Pgp`s are the triple mutant in the amino-proximal half of TM 12 (L975A-V981A-F983A) and the quadruple mutant (M986A-V988A-Q990A-V991A) (s). Login to comment
144 Photoaffinity labeling demonstrated that the triple mutant L975A-V981A-F983A displayed a significant reduction in binding of IAAP compared to wild-type Pgp which is consistent with its reduced drug transport ability (Figure 5b). Login to comment
147 The three double mutants L975A-V981A, L975A-F983A, and V981A-F983A were able to bind IAAP but somewhat less than wild-type Pgp as was also true for the single mutants investigated in this study (Figure 5b,c). Login to comment
153 Mutant MDR1s are double mutants L975A-V981A, L975A-F983A, and V981A-F983A (s). Login to comment
156 The double and single mutants displayed near wild-type levels of verapamil-stimulated ATPase activity except for L975A-V981A (Figure 6b). Login to comment
159 ATP binding was equivalent for wild-type MDR1 and the MDR1 mutants L975A-V981A-F983A as well as for M986A-V988A-Q990A-V991A (Figure 7). Login to comment
162 Vanadate-trapped [R-32P]-8-azido-ADP was significantly reduced in the triple mutant L975A-V981A-F983A (Figure 8b,c), consistent with the decrease a b c FIGURE 5: Photoaffinity labeling of wild-type and mutant Pgp`s. Login to comment
174 (a) pTM: cells infected with vTF 7-3 virus and transfected with the expression vector containing no MDR1 (pTM1) (negative control), WT (wild-type human MDR1), and mutant Pgp`s are the triple mutant in the amino-proximal half of TM 12 (L975A-V981A-F983A) and the quadruple mutant in the carboxy-terminal half of TM 12 (M986A- V988A-Q990A-V991A). Login to comment
176 Mutant MDR1s are the three double mutants L975A-V981A, L975A-F983A, and V981A-F983A. Login to comment
188 pTM: cells infected with vTF 7-3 virus and transfected with the expression vector containing no MDR1 (pTM1) (negative control), WT (wild-type human MDR1), the triple mutant in the amino-proximal half of TM 12 (L975A-V981A-F983A), the quadruple mutant in the carboxy-terminal half of TM 12 (M986A- V988A-Q990A-V991A), WT (wild-type human MDR1) in the presence of 250 µM EDTA and without MgCl2 to assess the specificity of the 170 kDa band representing Pgp as indicated with the arrow. Login to comment
193 (Middle panel) Vanadate-induced [R-32P]-8-azido-ADP labeling was performed at 37 °C. pTM: cells infected with vTF 7-3 virus and transfected with the expression vector containing no MDR1 (pTM1) (negative control), WT (wild-type human MDR1), the triple mutant in the amino-proximal half of TM 12 (L975A-V981A-F983A), and the quadruple mutant in the carboxy-terminal half of TM 12 (M986A- V988A-Q990A-V991A). Login to comment
227 To determine which combinations of these three residues of TM 12 predicted to lie in the outer leaflet were responsible for the loss of transport activity, we constructed double mutants (L975A-V981A, L975A-F983A, and V981A-F983A). Login to comment
228 The double mutants showed reduced drug transport suggesting that a change in any two of these three amino Table 2: Properties of Wild-Type and Mutant P-Glycoproteinsa photoaffinity labelinga ATP bindingb ATPase activityc wild-type ++++ ++++ ++++ L975A +++ n.d. +++ V981A +++ n.d. +++ F983A +++ n.d. +++ M986A n.d. n.d. n.d. V988A n.d. n.d. n.d. Q990A n.d. n.d. n.d. V991A n.d. n.d. n.d. L975A,V981A, F983A + ++++ + M986A, V988A, Q990A, V991A ++ ++++ ++ V981A, F983A +++ n.d. +++ L975A, F983A +++ n.d. +++ L975A, V981A +++ n.d. +++ a Symbols are noted as follows: ++++, wild-type activity; ++, impaired activity; +, residual activity; and n.d. not determined. b Photoaffinity labeling was done in HeLa crude membrane preparations using [125 I]iodoarylazidoprazosin. Login to comment
236 While no single residue is crucial, combinations of residues, especially V981A and F983A, affect binding of specific substrates such as daunomycin and rhodamine 123. Login to comment

[hide] New light on multidrug binding by an ATP-binding-c... Trends Pharmacol Sci. 2006 Apr;27(4):195-203. Epub 2006 Mar 20. Shilling RA, Venter H, Velamakanni S, Bapna A, Woebking B, Shahi S, van Veen HW
New light on multidrug binding by an ATP-binding-cassette transporter.
Trends Pharmacol Sci. 2006 Apr;27(4):195-203. Epub 2006 Mar 20., [PMID:16545467]

Abstract [show]
ATP-binding-cassette (ABC) multidrug transporters confer multidrug resistance to pathogenic microorganisms and human tumour cells by mediating the extrusion of structurally unrelated chemotherapeutic drugs from the cell. The molecular basis by which ABC multidrug transporters bind and transport drugs is far from clear. Genetic analyses during the past 14 years reveal that the replacement of many individual amino acids in mammalian multidrug resistance P-glycoproteins can affect cellular resistance to drugs, but these studies have failed to identify specific regions in the primary amino acid sequence that are part of a defined drug-binding pocket. The recent publication of an X-ray crystallographic structure of the bacterial P-glycoprotein homologue MsbA and an MsbA-based homology model of human P-glycoprotein creates an opportunity to compare the original mutagenesis data with the three-dimensional structures of transporters. Our comparisons reveal that mutations that alter specificity are present in three-dimensional 'hotspot' regions in the membrane domains of P-glycoprotein.

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58 Although mutation of only one of these residues (L975A, V981A and F983A) has no effect on the phenotype of the protein [20], double mutations either completely inhibit (V981A/F983A and L975A/V981A) or cause 50% inhibition (L975A/F983A) of Table 1. Login to comment
59 Published mutations in human and murine P-glycoprotein that alter drug transport in cells Location of mutation Mutation Refs Mutation Refs Mutation Refs Transmembrane helices H61A and others [14] I214L [60] L868W [59] G64R [15] P223A [65] I936A [21] L65R [15] S224P [60] F938A [21] Q139[H/P/R] [60] I306R [18] S939[A/C/T/Y/W/D/F] [21,22] G141V [17] F335A [16] T941A [21] G185V [61,62] V338A [66] Q942A [21] I186N [61] G338A [67,68] A943G [21] G187V [17] A339P [67,68] Y946A [21] G187E [60] G341A [66] S948A [21] A192T [60] S344[A/T/C/Y] [66] Y949A [21] F200L [60] N350I [19] C952A [21] F204S [60] P709A [65] F953A [21] R206L [60] G830V [17] L975A [20] W208G [60] I837L [23] F978A [16] K209E [60] N839I [23] V981A [20] L210I [60] I862F [19] F983A [20] T211P [60] L865F [19] F978A [16] V213A [60] P866A [65] N988D [59] Intracellular domain T169I [60] K177I [60] G288V [17] R170L [60] E180G [60] A931T [19] L171P [60] G181R [60] F934A [21] T172P [60] G183D [60] G935A [21] S176P [60] D184N [60] NBD D555N [63] K1076M [69] E1197Q [64] D558N [64] D1093N [64] D1203N [64] D592N [64] E1125Q [64] D1237N [64] E604Q [64] S1173A [70] E1249Q [64] Review TRENDS in Pharmacological Sciences Vol.27 No. Login to comment
61 The same mutations have either no effect (L975A/F983A and L975A/V981A) or cause up to 50% inhibition (V981A/ F983A) in the transport of bodipy-verapamil, calcein-AM and bodipy-taxol. Login to comment
57 Although mutation of only one of these residues (L975A, V981A and F983A) has no effect on the phenotype of the protein [20], double mutations either completely inhibit (V981A/F983A and L975A/V981A) or cause 50% inhibition (L975A/F983A) of Table 1. Login to comment

[hide] Molecular genetic analysis and biochemical charact... Semin Cell Dev Biol. 2001 Jun;12(3):247-56. Hrycyna CA
Molecular genetic analysis and biochemical characterization of mammalian P-glycoproteins involved in multidrug resistance.
Semin Cell Dev Biol. 2001 Jun;12(3):247-56., [PMID:11428917]

Abstract [show]
A variety of human cancers become resistant or are intrinsically resistant to treatment with conventional drug therapies. This phenomenon is due in large part to the overexpression of a 170 kDa plasma membrane ATP-dependent pump known as the multidrug resistance transporter or P-glycoprotein. P-glycoprotein is a member of the large ATP binding cassette (ABC) superfamily of membrane transporters. This review focuses on the use of structure-function analyses to elucidate further the mechanism of action of mammalian P-glycoproteins. Ultimately, a complete understanding of the mechanism is important for the development of novel strategies for the treatment of many human cancers.

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27 List of mutations in human, mouse and hamster P-gp`s that affect substrate specificity f aaa Mutation Regionb Sourcec Reference aa 78-97 EC 1 human MDR1 78 (ABC20)d Q128He TM 2 mouse mdr3 79 R138H IC 1 mouse mdr3 79 Q139H, R IC 1 mouse mdr3 79 G141V IC 1 human MDR1 25,80 Q145H IC 1 mouse mdr3 79 E155G, K IC 1 mouse mdr3 79 F159I IC 1 mouse mdr3 79 D174G IC 1 mouse mdr3 79 S176F, P IC 1 mouse mdr3 79 K177I IC 1 mouse mdr3 79 N179S IC1 mouse mdr3 79 N183S/G185V IC 1 human MDR1 81 G183D IC1 mouse mdr3 79 G185V IC 1 human MDR1 82-84 G187V IC 1 human MDR1 80 A192T TM 3 mouse mdr3 79 F204S EC 2 mouse mdr3 79 W208G EC 2 mouse mdr3 79 K209E EC 2 mouse mdr3 79 L210I TM 4 mouse mdr3 79 T211P TM 4 mouse mdr3 79 I214T TM 4 mouse mdr3 79 P223A TM 4 human MDR1 85 K285T IC 2 human MDR1 1 G288V IC 2 human MDR1 80 I299M, T319S, L322I, TM 5, EC3, IC 3 human MDR1 86 G324K, S351N V334 TM 6 human MDR1 1 F335A TM 6 human MDR1 25 F335 TM 6 human MDR1 87 V338A TM 6 human MDR1 88 G338A, A339P TM 6 hamster PGY 1 89,90 A339P TM 6 hamster PGY 1 90 G341V TM 6 human MDR1 88 K536R,Q N-NBD human MDR1 91 ERGA→DKGT N-NBD mouse mdr3 92 (aa 522-525) T578C N-NBD mouse mdr3 92 G812V IC 4 human MDR1 80 G830V IC 4 human MDR1 25,80 P866A TM 10 human MDR1 85 F934A TM 11 mouse mdr3 93 G935A TM 11 mouse mdr3 93 I936A TM 11 mouse mdr3 93 F938A TM 11 mouse mdr3 93 S939A TM 11 mouse mdr3 93 S939F TM 11 mouse mdr3 94,95 S941F TM 11 mouse mdr1 94,95 T941A TM 11 mouse mdr3 93 Q942A TM 11 mouse mdr3 93 Table 1-continued aaa Mutation Regionb Sourcec Reference A943G TM 11 mouse mdr3 93 Y946A TM 11 mouse mdr3 93 S948A TM 11 mouse mdr3 93 Y949A TM 11 mouse mdr3 93 C952A TM 11 mouse mdr3 93 F953A TM 11 mouse mdr3 93 F983A TM 12 human MDR1 96 L975A, V981A, F983A TM 12 human MDR1 96 M986A, V988A, TM 12 human MDR1 96 Q990A, V991A V981A, F983A TM 12 human MDR1 96 L975A, F983A TM 12 human MDR1 96 L975A, V981A TM 12 human MDR1 96 F978 TM 12 human MDR1 1 F978A TM 12 human MDR1 25 a aa, amino acid. Login to comment