ABCB1 p.Gly54Arg
| Predicted by SNAP2: | A: D (80%), C: D (75%), D: D (91%), E: D (91%), F: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (91%), P: D (91%), Q: D (91%), R: D (95%), S: D (75%), T: D (85%), V: D (91%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Arginines in the first transmembrane segment promo... J Biol Chem. 2008 Sep 5;283(36):24860-70. Epub 2008 Jul 2. Loo TW, Bartlett MC, Clarke DM
Arginines in the first transmembrane segment promote maturation of a P-glycoprotein processing mutant by hydrogen bond interactions with tyrosines in transmembrane segment 11.
J Biol Chem. 2008 Sep 5;283(36):24860-70. Epub 2008 Jul 2., 2008-09-05 [PMID:18596043]
Abstract [show]
A key goal is to correct defective folding of mutant ATP binding cassette (ABC) transporters, as they cause diseases such as cystic fibrosis. P-glycoprotein (ABCB1) is a useful model system because introduction of an arginine at position 65 of the first transmembrane (TM) segment could repair folding defects. To determine the mechanism of arginine rescue, we first tested the effects of introducing arginines at other positions in TM1 (residues 52-72) of a P-glycoprotein processing mutant (G251V) that is defective in folding and trafficking to the cell surface (20% maturation efficiency). We found that arginines introduced into one face of the TM1 helix (positions 52, 55, 56, 59, 60, 62, 63, 66, and 67) inhibited maturation, whereas arginines on the opposite face of the helix promoted (positions 64, 65, 68, and 71) or had little effect (positions 61, and 69) on maturation. Arginines at positions 61, 64, 65, and 68 appeared to lie close to the drug binding sites as they reduced the apparent affinity for drug substrates such as vinblastine and verapamil. Therefore, arginines that promoted maturation may face an aqueous drug translocation pathway, whereas those that inhibited maturation may face the lipid bilayer. The highest maturation efficiencies (60-85%) were observed with the Arg-65 and Arg-68 mutants. Mutations that removed hydrogen bond acceptors (Y950F/Y950A or Y953F/Y953A) in TM11 predicted to lie close to Arg-65 or Arg-68 inhibited maturation but did not affect maturation of the G251V parent. Therefore, arginine may rescue defective folding by promoting packing of the TM segments through hydrogen bond interactions.
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No. Sentence Comment
151 By contrast, 12 of the mutants (V53R, G54R, T55R, L56R, A57R, A58R, I59R, I60R, G62R, A63R, P66R, and F72R) showed little or no rescue in the presence of drug substrates.
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ABCB1 p.Gly54Arg 18596043:151:38
status: NEW[hide] Mutations in the cyp51A gene and susceptibility to... J Antimicrob Chemother. 2005 Jan;55(1):31-7. Epub 2004 Nov 24. Chen J, Li H, Li R, Bu D, Wan Z
Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma.
J Antimicrob Chemother. 2005 Jan;55(1):31-7. Epub 2004 Nov 24., [PMID:15563516]
Abstract [show]
OBJECTIVES: To monitor changes in itraconazole susceptibility of isolates from a patient undergoing treatment for pulmonary Aspergillus infection and relate these changes to genotypic/phenotypic alterations. METHODS: Six Aspergillus fumigatus isolates were serially recovered from the patient. Itraconazole MICs were determined by Etest and NCCLS methodology. Growth characteristics and phenotype were monitored. Molecular analysis included random amplified polymorphic DNA (RAPD) assay and sequencing of the cyp51A gene. RESULTS: The MIC of itraconazole against the first isolate before treatment was 0.25 mg/L; the MIC against the second isolate, recovered after 6 months of itraconazole therapy, was >16 mg/L; and that against the third isolate, obtained 2 months after discontinuation of the therapy, was 0.5 mg/L. The MIC against the last three isolates, acquired after restoration of itraconazole therapy for 4-7 months, was >16 mg/L. The six isolates shared identical band patterns of RAPD assay using four primers and the same sequence in intertranscribed spacers (ITS). Therefore, the six isolates were likely to be the same strain of A. fumigatus, and mutations involving itraconazole resistance possibly occurred in these isolates after prolonged itraconazole therapy. Sequencing of the cyp51A gene in the coding region revealed a mutation of M220I in cytochrome P450 sterol 14-alpha-demethylase in the second resistant isolate and a mutation of G54R in the last three resistant isolates. Expression changes of some pump genes, such as MDR3, may also, in part, be related to the resistance to itraconazole. CONCLUSIONS: We conclude that resistance of A. fumigatus to itraconazole occurred in a patient treated with the drug, and the resistance may result from mutations in the cyp51A gene-the gene encoding the target enzyme for itraconazole.
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No. Sentence Comment
133 (b) Another point transition mutation of G160A, which converts glycine into arginine at residue 54 (G54R) in cytochrome P450 sterol 14-a-demethylase, was found in AF4, 5 and 6.
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ABCB1 p.Gly54Arg 15563516:133:100
status: NEW137 The mutation M220I was found in resistant isolate AF2, and the mutation G54R was found in resistant isolates AF4, AF5 and AF6.
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ABCB1 p.Gly54Arg 15563516:137:72
status: NEW148 The G54R mutation is located in a very conserved region, possibly involved in inhibitor- or substrate-induced structure changes in the enzyme molecule.
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ABCB1 p.Gly54Arg 15563516:148:4
status: NEW