ABCC1 p.Thr1337Ala
| Predicted by SNAP2: | A: N (82%), C: N (61%), D: D (63%), E: D (71%), F: D (66%), G: D (53%), H: D (63%), I: D (59%), K: D (75%), L: D (53%), M: N (66%), N: N (53%), P: D (66%), Q: D (59%), R: D (75%), S: N (72%), V: N (57%), W: D (71%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, V: D, W: D, Y: D, |
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[hide] Structural and functional properties of human mult... Curr Med Chem. 2011;18(3):439-81. He SM, Li R, Kanwar JR, Zhou SF
Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1).
Curr Med Chem. 2011;18(3):439-81., [PMID:21143116]
Abstract [show]
Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.
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No. Sentence Comment
816 There are at least 15 naturally occurring mutations identified in MRP1/ABCC1, including Cys43Ser in TM1, Thr73Ile in CL1, Ser92Phe in TM2, Arg230Asn in L0, Val353Met at TM6/TM7 interface, Arg433Ser in TM8, Gly671Val in TM11, Arg723Gln located between the Walker A and Walker B motifs of NBD1, Ala861Thr at NBD1/TM12 interface, Ala989Thr in TM12, Cys1047Ser in TM13, Arg1058Gln in CL7, Val1146Ile in CL7, Thr1337Ala between the Walker A and Walker B motifs of NBD2, and Thr1401Met, and many of them have been found to affect its transport activity [171, 362, 363, 366, 367, 377-384].
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ABCC1 p.Thr1337Ala 21143116:816:404
status: NEW[hide] Importance of ABCC1 for cancer therapy and prognos... Drug Metab Rev. 2014 Aug;46(3):325-42. doi: 10.3109/03602532.2014.901348. Epub 2014 Mar 26. Kunicka T, Soucek P
Importance of ABCC1 for cancer therapy and prognosis.
Drug Metab Rev. 2014 Aug;46(3):325-42. doi: 10.3109/03602532.2014.901348. Epub 2014 Mar 26., [PMID:24670052]
Abstract [show]
Multidrug resistance presents one of the most important causes of cancer treatment failure. Numerous in vitro and in vivo data have made it clear that multidrug resistance is frequently caused by enhanced expression of ATP-binding cassette (ABC) transporters. ABC transporters are membrane-bound proteins involved in cellular defense mechanisms, namely, in outward transport of xenobiotics and physiological substrates. Their function thus prevents toxicity as carcinogenesis on one hand but may contribute to the resistance of tumor cells to a number of drugs including chemotherapeutics on the other. Within 48 members of the human ABC superfamily there are several multidrug resistance-associated transporters. Due to the well documented susceptibility of numerous drugs to efflux via ABC transporters it is highly desirable to assess the status of ABC transporters for individualization of treatment by their substrates. The multidrug resistance associated protein 1 (MRP1) encoded by ABCC1 gene is one of the most studied ABC transporters. Despite the fact that its structure and functions have already been explored in detail, there are significant gaps in knowledge which preclude clinical applications. Tissue-specific patterns of expression and broad genetic variability make ABCC1/MRP1 an optimal candidate for use as a marker or member of multi-marker panel for prediction of chemotherapy resistance. The purpose of this review was to summarize investigations about associations of gene and protein expression and genetic variability with prognosis and therapy outcome of major cancers. Major advances in the knowledge have been identified and future research directions are highlighted.
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159 NCBI ID Reference Amino acid exchange Nucleotide exchange Location Function MAFa rs41395947 Cys43Ser G128C Exon 2 Non-synonymous Unknown rs41494447 Thr73Ile C218T Exon 2 Non-synonymous T &#bc; 0.003 rs8187844 Ser92Phe C257T Exon 3 Non-synonymous T &#bc; 0.004 rs8187848 Arg230Gln G689A Exon 7 Non-synonymous A &#bc; 0.009 rs2230669 Pro272Pro G816A Exon 8 Synonymous A &#bc; 0.037 rs246221 Val275Val T825C Exon 8 Synonymous C &#bc; 0.301 rs35592 non-coding T-176C Intron 9 Non-coding C &#bc; 0.257 rs60782127 Arg433Ser G1299T Exon 10 Non-synonymous T &#bc; 0.004 rs35605 Leu562Leu T1684C Exon 13 Synonymous T &#bc; 0.173 rs112282109 Arg633Gln G1898A Exon 14 Non-synonymous A &#bc; 0.004 rs45511401 Gly671Val G2012T Exon 16 Non-synonymous T &#bc; 0.050 rs4148356 Arg723Gln G2168A Exon17 Non-synonymous A &#bc; 0.027 rs35529209 Ala989Thr G2965A Exon 22 Non-synonymous Unknown rs13337489 Cys1047Ser G3140C Exon 23 Non-synonymous C &#bc; 0.000 rs41410450 Arg1058Gln G3173A Exon 23 Non-synonymous Unknown rs2238476 non-coding G-1960A Intron 23 Non-coding T &#bc; 0.062 rs2230671 Ser1334Ser G4002A Exon 28 Synonymous T &#bc; 0.208 rs28364006 Thr1337Ala A4009G Exon 28 Non-synonymous Unknown rs369410659 Ser1512Leu C4535T Exon 31 Non-synonymous Unknown a Minor allele frequencies for Caucasinans in dbSNP based on HapMap-CEU population or 1000 genomes.
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ABCC1 p.Thr1337Ala 24670052:159:1135
status: NEW[hide] Genetic variation of the ABC transporter gene ABCC... BMC Genet. 2015 Sep 23;16(1):114. doi: 10.1186/s12863-015-0271-3. Slomka M, Sobalska-Kwapis M, Korycka-Machala M, Bartosz G, Dziadek J, Strapagiel D
Genetic variation of the ABC transporter gene ABCC1 (Multidrug resistance protein 1-MRP1) in the Polish population.
BMC Genet. 2015 Sep 23;16(1):114. doi: 10.1186/s12863-015-0271-3., [PMID:26395522]
Abstract [show]
BACKGROUND: Multidrug resistance-associated protein 1 (MRP1), encoded by the ABCC1 gene, is an ATP-binding cassette transporter mediating efflux of organic anions and xenobiotics; its overexpression leads to multidrug resistance. In this study, 30 exons (from 31 in total) of the ABCC1 gene as well as and their flanking intron sequences were screened for genetic variation, using the High Resolution Melting (HRM) method, for 190 healthy volunteers representing the Polish population. Polymorphism screening is an indispensable step in personalized patient therapy. An additional targeted SNP verification study for ten variants was performed to verify sensitivity of the scanning method. RESULTS: During scanning, 46 polymorphisms, including seven novel ones, were found: one in 3' UTR, 21 in exons (11 of them non-synonymous) and 24 in introns, including one deletion variant. These results revealed some ethnic differences in frequency of several polymorphisms when compared to literature data for other populations. Based on linkage disequilibrium analysis, 4 haplotype blocks were determined for 9 detected polymorphisms and 12 haplotypes were defined. To capture the common haplotypes, haplotype-tagging single nucleotide polymorphisms were identified. CONCLUSIONS: Targeted genotyping results correlated well with scanning results; thus, HRM is a suitable method to study genetic variation in this model. HRM is an efficient and sensitive method for scanning and genotyping polymorphic variants. Ethnic differences were found for frequency of some variants in the Polish population compared to others. Thus, this study may be useful for pharmacogenetics of drugs affected by MRP1-mediated efflux.
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154 Bold variants signifies the ones which were validated by genotyping results Table 3 Summary of ABCC1 selected SNPs genotyping by HRM and comparing them with scanning results dbSNP ID Variant residue NM_004996.3: Intron/amino acid residue NP_004987.2: Observed genotypesa (n) HWE exact test P-valueb MAFc (genotyping) MAFc (scanning) Chi-square test P-valued R/R R/V V/V rs41395947 c.128G > C p.Cys43Se 380 0 0 1 - - - rs2230669 c.816G > A p.Pro272= 362 18 0 1 (A) 0.024 (A) 0.043 0.079 rs246221 c.825 T > C p.Val275 197 160 23 0.243 (C) 0.271 (C) 0.309 0.187 rs8187852 c.1057G > A p.Val353Met 379 0 0 1 - - - rs35587 c.1062 T > C p.Asn354= 204 142 33 0.247 (C) 0.274 (C) 0.332 0.044 rs35588 c.1218 + 8A > G Intron 190 160 30 0.709 (G) 0.289 (G) 0.325 0.214 rs60782127 c.1299G > T p.Arg433Ser 373 6 0 1 (T) 0.008 (T) 0.005 0.623 rs35605 c.1684 T > C p.Leu562= 13 105 262 0.588 (T) 0.172 (T) 0.130 0.063 rs8187858 c.1704C > T p.Tyr568= 325 55 0 0.242 (T) 0.072 (T) 0.087 0.374 rs45511401 c.2012G > T p.Gly671Val 346 28 3 0.007 (T) 0.045 (T) 0.077 0.038 rs4148356 c.2168G > A p.Arg723Gln 360 19 0 1 (A) 0.025 (A) 0.024 0.888 rs45517537 c.2581G > A p.Ala861Thr 380 0 0 1 - - - rs35529209 c.2965G > A p.Ala989Thr 378 0 0 1 - - - rs13337489 c.3140G > C p.Cys1047Ser 380 0 0 1 - - - rs28706727 c.3436G > A p.Val1146Ile 380 0 0 1 - - - rs2230671 c.4002G > A p.Ser1334= 204 140 32 0.296 (A) 0.271 (A) 0.277 0.850 rs28364006 c.4009A > G p.Thr1337Ala 380 0 0 1 - - - a Number of genotypes detected during this study, R - reference allele, V - variant allele. b P-value is consistent with Hardy-Weinberg equilibrium if P > 0.001. c Minor allele shown in brackets with its frequency.
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ABCC1 p.Thr1337Ala 26395522:154:1429
status: NEW