ABCC1 p.Ala893Pro
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PMID: 18154452
[PubMed]
Sharom FJ et al: "ABC multidrug transporters: structure, function and role in chemoresistance."
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312
However, the nonsynonymous mutations of G2677T/A/C, which result in the amino acid changes A893S, A893T and A893P, gave changes in both substrate specificity and ATPase kinetic properties as measured with 41 different test compounds [139].
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ABCC1 p.Ala893Pro 18154452:312:108
status: NEW
PMID: 18851956
[PubMed]
Rebecchi IM et al: "ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment."
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26
The G2677T/A/C (rs2032582) is a non-synonymous polymorphism in the exon 21 with three distinct amino acid changes (Ala893Ser, Ala893Thr, and Ala893Pro, respectively) that is located at the transmembrane domain of the protein and it has a great impact on both the activity and the substrate specificity of ABCB1 toward different test compounds [10].
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ABCC1 p.Ala893Pro 18851956:26:141
status: NEW
PMID: 20138191
[PubMed]
Ishikawa T et al: "Emerging new technologies in Pharmacogenomics: rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1)."
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352
While the A893P variant (2677GNC) is a rare mutation, triallelic SNPs of 2677G, 2677 T, and 2677A exhibit wide ethnic differences in allele frequency (Fig. 1A).
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ABCC1 p.Ala893Pro 20138191:352:10
status: NEW363 The A893P (Pro893) variant is a rare mutation (rs2032582) recorded in the NCBI dbSNP data base.
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ABCC1 p.Ala893Pro 20138191:363:4
status: NEW413 To understand the molecular mechanisms underlying the observed differences in the ATPase activity among ABCB1 WT, A893P, A893S, and A893T (Sakurai et al., 2007), we performed MD simulation based on the homology model of ABCB1.
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ABCC1 p.Ala893Pro 20138191:413:114
status: NEW441 The initial three-dimensional structure of each variant protein (A893S, A893T, or A893P) was deduced from the ABCB1 structure template by using the LEAP module in the AMBER (Assisted model building and energy refinement) simulation package.
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ABCC1 p.Ala893Pro 20138191:441:82
status: NEW452 Thus, MD calculation was performed to simulate the movement of the intracellular loop located between TM10 and TM11 for each variant protein (A893S, A893T, or A893P) as well as the WT.
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ABCC1 p.Ala893Pro 20138191:452:159
status: NEW453 Fig. 4B demonstrates the loop structures of WT, A893S, A893T, or A893P calculated from the trajectory data of MD simulations at 310 K (37˚C) for 3 ns.
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ABCC1 p.Ala893Pro 20138191:453:65
status: NEW454 Our MD simulation clearly shows that multiple kinks are formed in the intracellular loop between TM10 and TM11 in the A893P protein.
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ABCC1 p.Ala893Pro 20138191:454:118
status: NEW455 The RMSF value of alpha carbon of each amino acid residue was calculated from the trajectory data for the intracellular loop of WT, A893S, A893T, and A893P.
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ABCC1 p.Ala893Pro 20138191:455:150
status: NEW456 The A893P variant exhibited notably great fluctuations in the intracellular loop, in particular, at the region of amino acids 910 - 920 (data not shown).
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ABCC1 p.Ala893Pro 20138191:456:4
status: NEW457 It is suggested that the A893P mutation promotes multiple kinks in this cytoplasmic helical region and modify the interaction of coupling helix 2 with the ATP-binding domain.
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ABCC1 p.Ala893Pro 20138191:457:25
status: NEW459 The A893P variant (2677GNC), a rare mutation, exhibited markedly high activity of ATPase toward different test compounds (Fig. 5).
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ABCC1 p.Ala893Pro 20138191:459:4
status: NEW461 The MD simulation results may provide an explanation, in part, for the effect of the A893P mutation on ATP hydrolysis.
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ABCC1 p.Ala893Pro 20138191:461:85
status: NEW478 To functionally validate the non-synonymous polymorphisms of ABCB1 (P-glycoprotein/MDR1) in vitro, we generated SNP variant forms (i.e., S400N, R492C, R669C, I849M, A893P, A893S, A893T, M986V, A999T, P1051A, and G1063A; refer to Fig. 6) and expressed them in Sf9 cells.
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ABCC1 p.Ala893Pro 20138191:478:165
status: NEW480 The effect of test compounds on the ATPase activity of ABCB1 WT, A893P, A893S, and A893T.
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ABCC1 p.Ala893Pro 20138191:480:65
status: NEW500 SNP Km Vmax Vmax / Km (µM) (nmol/min/mg protein) WT 5.8±2.3 62.4±7.8 10.8 S400N 5.8±2.8 46.7±5.3⁎⁎ 8.0 R492C 5.6±1.9 49.6±10.0⁎ 8.9 R669C 3.2±1.6⁎ 64.7±6.9 20.1 I849M 1.5±0.7⁎⁎ 80.3±9.5⁎⁎ 51.8 A893P 1.5±0.5⁎⁎ 405.2±16.5⁎⁎ 274.6 A893S 11.1±5.4 43.1±7.1⁎⁎ 3.9 A893T 4.3±1.4 98.9±9.5⁎⁎ 22.9 M986V 5.1±1.1 114.9±13.6⁎⁎ 22.5 A999T 2.0±0.8⁎⁎ 143.1±21.2⁎⁎ 70.9 P1051A 6.2±3.0 52.1±13.6 8.4 G1063A 6.2±3.7 117.9±16.4⁎⁎ 19.0 Data are expressed as mean±S.D., n=6.
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ABCC1 p.Ala893Pro 20138191:500:304
status: NEW