Homology modeling of breast cancer resistance protein (ABCG2)

Hazai, Eszter; Bikádi, Zsolt

doi:10.1016/j.jsb.2007.12.001

Cited by 85 publications

(72 citation statements)

References 52 publications

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“…Phe-431 is thought to be located near the boundary region between the extracellular side and the second transmembrane domain of BCRP, (44,45) but it is still unclear whether Phe-431 is associated with the substrate-binding pocket. Li et al reported that another mutant, F431S-BCRP, is still functional because pheophorbide A transport by F431S-BCRP was completely suppressed by FTC.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

et al. 2010

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Sunitinib malate (Sutent, SU11248) is a small-molecule multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Some TKIs can overcome multidrug resistance conferred by ATP-binding cassette transporter, P-glycoprotein (P-gp) ⁄ ABCB1, multidrug resistance-associated protein 1 (MRP1) ⁄ ABCC1, and breast cancer resistance protein (BCRP) ⁄ ABCG2. Here, we analyzed the effects of sunitinib on P-gp and on wild-type and germ-line mutant BCRPs. Sunitinib remarkably reversed BCRP-mediated and partially reversed P-gp-mediated drug resistance in the respective transfectants. The in vitro vesicle transport assay indicated that sunitinib competitively inhibited BCRP-mediated estrone 3-sulfate transport and P-gp-mediated vincristine transport. These inhibitory effects of sunitinib were further analyzed in Q141K-, R482G-, R482S-, and F431L-variant BCRPs. Intriguingly, the F431L-variant BCRP, which is expressed by a germ-line mutant allele 1291T>C, was almost insensitive to both sunitinib-and fumitremorgin C (FTC)-mediated inhibition in a cell proliferation assay. Sunitinib and FTC did not inhibit 125 I-iodoarylazidoprazosin-binding to F431L-BCRP. Thus, residue Phe-431 of BCRP is important for the pharmacological interaction with sunitinib and FTC. Collectively, this is the first report showing a differential effect of a germ-line variation of the BCRP ⁄ ABCG2 gene on the pharmacological interaction between small-molecule TKIs and BCRP. These findings would be useful for improving our understanding of the pharmaceutical effects of sunitinib in personalized chemotherapy. (Cancer Sci 2010; 101: 1493-1500 T he ATP-binding cassette (ABC) transporter proteins, particularly P-glycoprotein (P-gp ⁄ ABCB1), multidrug resistance-associated protein 1 (MRP1 ⁄ ABCC1), and breast cancer resistance protein (BCRP ⁄ MXR ⁄ ABCP ⁄ ABCG2) have been extensively studied as key molecules that are involved in the multidrug-resistant phenotype of cancer cells.(1,2) P-gp effluxes various anticancer agents including vincristine (VCR), paclitaxel (PTX), doxorubicin (DOX), and mitoxantrone (MXR). (1,3) BCRP is referred to as a half-type ABC transporter that functions as a homodimer and transports anticancer agents such as topotecan, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), methotrexate, and MXR out of cells. Many compounds have been tested for their ability to overcome ABC transporter-mediated drug resistance. Verapamil, cyclosporine A (CsA), and other compounds have been identified as inhibitors of P-gp, (5,6) while fumitremorgin C (FTC), tamoxifen derivatives, and certain flavonoids inhibit BCRP.(7-10) Verapamil, for example, directly interacts with P-gp and competitively interferes with transporter-substrate binding. (11) Co-administration of inhibitory compounds would be expected to overcome unwanted anticancer drug resistance during chemotherapy, but is also suspected to affect the pharmacokinetics and pharmacodynamics of substrate anticancer drugs....

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Section: Discussionmentioning

confidence: 99%

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

et al. 2010

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“…Since no atomic level crystal structure is available for any closely related ABCG-type proteins, the localization of amino acids in the transmembrane helices cannot be properly estimated. The homology models constructed on the basis of unrelated ABC transporters (Hazai & Bikadi, 2008;Li et al, 2007) are contradictory and cannot be properly applied for devising site-directed mutagenesis. Still, information obtained by site-directed mutagenesis and related to potential lipid sensors and lipid-binding sites in ABCG2 is already available regarding the interaction of cholesterol and some sterol compounds with the transporter.…”

Section: Article In Pressmentioning

confidence: 99%

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Hegedüs

Telbisz

Hegedüs

et al. 2015

Advances in Cancer Research

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“…The EC50 of distant by about 40 residues from the beginning of TMD, which is similar to the length of the intracellular loops in crystallized bacterial Sav1866 [12] and eukaryotic P-glycoproteins [10,11]. However, it not known if the presence of the C2-sequence might compensate the lack of a long intracellular loop, as shown in the human ABCG2 molecular model [36], or if such a multidrug homodimeric half-transporter might require additional interactions than full-transporters such as ABCB1 and ABCC1. It is not either known if the absence of such a C2-sequence in lower eukaryotes might be correlated to differences in the regulation of activity or in structural divergence of these ABCG2 homologs.…”

Section: Alterations Of the Interaction With Different Types Of Drug-mentioning

confidence: 74%

The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport

Macalou

Robey

Gozzi

et al. 2015

Cell. Mol. Life Sci.

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Abstract:The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotidebinding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C motif/ABC signature present in all ABC nucleotidebinding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an α-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2 sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationmitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux. Running title: Linker region of human ABCG2Keywords: ABC transporter, breast cancer resistance protein/ABCG2, ATP hydrolysis, C motif/ABC signature, drug efflux coupling, specific sequence. Abbreviations: ABC, ATP-binding cassette; MDR, multidrug resistanceRevised Manuscript Click here to download Manuscript CMLS_C2_R1.docx 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Click here to view linked References AbstractThe ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotidebinding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted.Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an -helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation.These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux.

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Homology modeling of breast cancer resistance protein (ABCG2)

Cited by 85 publications

References 52 publications

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport

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