ABCMdb

PMID: 16545467

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., [PubMed]

Sentences

No. Mutations Sentence Comment

47 ABCB1 p.His61Arg The only exception is the introduction of a positively charged residue at position 61 (H61R), which decreases resistance to daunomycin. Login to comment 48 ABCB1 p.His61Arg The only exception is the introduction of a positively charged residue at position 61 (H61R), which decreases resistance to daunomycin. Login to comment 51 ABCB1 p.Val338Ala V338A confers wild-type levels of resistance to actinomycin D, increases resistance to daunomycin and colchicine, and reduces resistance to vinblastine. Login to comment 52 ABCB1 p.Val338Ala ABCB1 p.Gly341Ala V338A confers wild-type levels of resistance to actinomycin D, increases resistance to daunomycin and colchicine, and reduces resistance to vinblastine. Login to comment 53 ABCB1 p.Ile306Arg ABCB1 p.Gly341Ala The G341A mutation almost completely abolishes the resistance to colchicine and daunomycin, but the resistance to vinblastine and actinomycin D remains at wild-type levels [17]. Login to comment 54 ABCB1 p.Ile306Arg Residue I306 is at the interface between TMH5 and TMH6, and its replacement by Arg (I306R) results in a 50-fold reduction in affinity for verapamil but the affinity for rhodamine B and colchicines is unaltered [18]. Login to comment 57 ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala 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 58 ABCB1 p.Gly288Val ABCB1 p.Pro866Ala ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Gly185Val ABCB1 p.Phe978Ala ABCB1 p.Phe978Ala ABCB1 p.Gly187Val ABCB1 p.Thr941Ala ABCB1 p.Phe938Ala ABCB1 p.Phe204Ser ABCB1 p.Val338Ala ABCB1 p.Pro223Ala ABCB1 p.Phe335Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala ABCB1 p.Gly830Val ABCB1 p.Asp555Asn ABCB1 p.Asn839Ile ABCB1 p.Lys1076Met ABCB1 p.Ile306Arg ABCB1 p.Ile186Asn ABCB1 p.Pro709Ala ABCB1 p.Gly141Val ABCB1 p.Gly341Ala ABCB1 p.His61Ala ABCB1 p.Leu171Pro ABCB1 p.Gly187Glu 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 ABCB1 p.Gly288Val ABCB1 p.Pro866Ala ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Gly185Val ABCB1 p.Phe978Ala ABCB1 p.Phe978Ala ABCB1 p.Gly187Val ABCB1 p.Thr941Ala ABCB1 p.Phe938Ala ABCB1 p.Phe204Ser ABCB1 p.Val338Ala ABCB1 p.Pro223Ala ABCB1 p.Phe335Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala ABCB1 p.Gly830Val ABCB1 p.Asp555Asn ABCB1 p.Asn839Ile ABCB1 p.Lys1076Met ABCB1 p.Ile306Arg ABCB1 p.Ile186Asn ABCB1 p.Pro709Ala ABCB1 p.Gly141Val ABCB1 p.Gly341Ala ABCB1 p.His61Ala ABCB1 p.Leu171Pro ABCB1 p.Gly187Glu 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 60 ABCB1 p.Phe978Leu Another replacement in this cluster in TMH12 (F978L) reduces resistance to colchicine and daunomycin but has no significant effect on the resistance to vinblastine and actinomycin D [16]. Login to comment 61 ABCB1 p.Val981Ala ABCB1 p.Val981Ala ABCB1 p.Phe983Ala ABCB1 p.Phe983Ala ABCB1 p.Leu975Ala ABCB1 p.Leu975Ala 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 62 ABCB1 p.Phe978Leu Another replacement in this cluster in TMH12 (F978L) reduces resistance to colchicine and daunomycin but has no significant effect on the resistance to vinblastine and actinomycin D [16]. Login to comment 65 ABCB1 p.Asn839Ile Hotspot IIB Change-in-specificity mutations also occur as a result of spontaneous mutations (I837L and N839I) in TMH9 [23]. Login to comment 67 ABCB1 p.Asn839Ile Hotspot IIB Change-in-specificity mutations also occur as a result of spontaneous mutations (I837L and N839I) in TMH9 [23]. Login to comment 76 ABCB1 p.Leu975Cys ABCB1 p.Phe942Cys ABCB1 p.Thr945Cys ABCB1 p.Ile868Cys ABCB1 p.Leu339Cys ABCB1 p.Ile340Cys ABCB1 p.Ala342Cys ABCB1 p.Ala841Cys ABCB1 p.Val982Cys ABCB1 p.Val981Cys ABCB1 p.Gly984Cys ABCB1 p.Ser222Cys Single-cysteine mutants in human P-glycoprotein that are protected from cross-linking to cysteine-reactive MTS substrate analogues by the non-reactive substratea P-glycoprotein residueb Corresponding residue in V. cholera MsbA Cysteine-reactive substrate I340C (6) G293 MTS-rhodamine A841C (9) A151 MTS-rhodamine L975C (12) T285 MTS-rhodamine V981C (12) M291 MTS-rhodamine V982C (12) F292 MTS-rhodamine S222C (4) A175 MTS-verapamil L339C (6) M291 MTS-verapamil A342C (6) M295 MTS-verapamil I868C (10) F180 MTS-verapamil F942C (11) Q256 MTS-verapamil T945C (11) A259 MTS-verapamil G984C (12) L294 MTS-verapamil a Data adapted from [24,25]. Login to comment 78 ABCB1 p.Leu975Cys ABCB1 p.Phe942Cys ABCB1 p.Thr945Cys ABCB1 p.Ile868Cys ABCB1 p.Leu339Cys ABCB1 p.Ile340Cys ABCB1 p.Ala342Cys ABCB1 p.Ala841Cys ABCB1 p.Val982Cys ABCB1 p.Val981Cys ABCB1 p.Gly984Cys ABCB1 p.Ser222Cys Single-cysteine mutants in human P-glycoprotein that are protected from cross-linking to cysteine-reactive MTS substrate analogues by the non-reactive substratea P-glycoprotein residueb Corresponding residue in V. cholera MsbA Cysteine-reactive substrate I340C (6) G293 MTS-rhodamine A841C (9) A151 MTS-rhodamine L975C (12) T285 MTS-rhodamine V981C (12) M291 MTS-rhodamine V982C (12) F292 MTS-rhodamine S222C (4) A175 MTS-verapamil L339C (6) M291 MTS-verapamil A342C (6) M295 MTS-verapamil I868C (10) F180 MTS-verapamil F942C (11) Q256 MTS-verapamil T945C (11) A259 MTS-verapamil G984C (12) L294 MTS-verapamil a Data adapted from [24,2]. Login to comment