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Drug resistance transporter, ABCG2 (MXR; ABCP) (human breast cancer resistance protein, BCRP) (Moitra et al., 2011). It exports urate and haem in haempoietic cells (Latunde-Dada et al., 2006) as well as cytotoxic agents (mitoxantrone, flavopiridol, methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, topotecan, rosurvastatin, and resveratrol), fluorescent dyes (Hoechst 33342) and other toxic substances (PhIP and pheophorbide a) (Özvegy-Laczka et al., 2005; Nigam 2015). It also transports folate and sterols: estradiol, and probably cholesterol, progesterone, testosterone and tamoxifen (Janvilisri et al., 2003; Breedveld et al., 2007). It is a homotetramer (Xu et al., 2004). It forms a homodimer bound via a disulfide bond at Cys-603 which stabilizes the protein against ubiquitin-mediated degradation in proteosomes (Wakabayashi et al., 2007), and can for dodecamers with 12 subunits (Xu et al. 2007). It has 6 established TMSs with the N- and C- termini inside (Wang et al., 2008). The following drugs are exported from human breast cancer cell line MCF-7: miloxantrone, daunorubicin, doxorubicin and rhodamine123). Also transports reduced folates and mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). It is an active glutathione efflux pump (Brechbuhl et al., 2010). Mutations in ABCG2 cause hyperuricemia and gout , which led to the identification of urate as a physiological subsrate for ABCG2; it catalyzes elimination of urate across the renal tubular apical membrane (Prestin et al. 2014). Zafirlukast antagonizes ABCG2 multidrug resistance (Sun et al., 2012). Inhibited by Sildenafil (Shi et al., 2011) and lapatinib derivatives (Sodani et al., 2012).  Mutation of basic residues can increase or decrease drug efflux activities (Cai et al. 2010).  A substrate of ABCG2 is d-luciferin, allowing bioluminescent immaging of drug efflux across the blood-brain barrier.  Inhibitors include Ko143, gefetinib and nilotinib (Bakhsheshian et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  Telabinib reverses chemotheraputic MDR mediated by ABCG2 (Sodani et al. 2014).  Residues involved in protein trafficking and drug transport activity have been identified (Haider et al. 2015).  The 3-d structure in the inward facing conformation has been solved (Rosenberg et al. 2015). Durmus et al. 2015 and Westover and Li 2015 have reviewed BCRP-mediated transport of cancer chemotheraputic agents.  A role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux has been proposed (Macalou et al. 2015).  Functions at the blood:placenta barrier of the mouse (Kumar et al. 2016). The Q141K variant exhibits decreased functional expression and thus increased drug accumulation and decreased urate secretion, and the R482 position, which plays a role the substrate specificity, is located in one of the substrate binding pockets (László et al. 2016). Naturally occurring single nucleotide polymorphisms in humans giving rise to amino acyl residue substitutions in the transmembrane domains result in impared transport of Lucifer Yellow and estrone sulfate (Sjöstedt et al. 2017). A cryoEM structure revealed two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between TMSs. A multidrug recognition and transport mechanism was proposed, and disease-causing single nucleotide polymorphisms were rationalized. The structural basis of cholesterol recognition by G-subfamily ABC transporters was also revealed (Taylor et al. 2017). Catalyzes efflux of ochratoxin A (OTA) (Qi et al. 2017). Penylheteroaryl-phenylamide scaffold allows ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a highest potency (IC50=61nM)), selectivity, low intrinsic toxicity, and it reversed the ABCG2-mediated drug resistance at 0.1muM (Köhler et al. 2018). ABCG2 acts in concert with ABCA1, ABCB1 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). Inhibited by dacomitinib (Fan et al. 2018). A specific inhibitor, CCTA-1523, is a potent, selective and reversible modulator of ABCG2 (Patel et al. 2017). Exports uric acid (urate), and its loss promotes onset of hyperuricemia.  It has potential as a regulator of Gout (Fujita and Ichida 2018). High resolution cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar have been solved (Jackson et al. 2018). Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the TMSs (Jackson et al. 2018). Multiple drug binding pockets and residues involved in binding have been identified (Cox et al. 2018). The third transmembrane helix and adjacent regions of ABCG2 may interact with AT1 receptor antagonists, giving rise to drug-drug interactions in multi-drug regimens (Ripperger et al. 2018). The system is inhibitied by hetero aryl phenyl inhititors (Köhler et al. 2018). It is present in the blood-brain, blood-testis and maternal-fetal barriers, and cryoEM of a mutant shows the protein in a substrate-bound pre-translocation state and an ATP-bound post-translocation state (Manolaridis et al. 2018). A single molecule of estrone-3-sulfate (E1S) is bound in a central, hydrophobic, cytoplasm-facing cavity about halfway across the membrane. Only one molecule of E1S can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains (Manolaridis et al. 2018). This shows how the energy of ATP binding extrudes E1S and other substrates, and suggests that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors. Its structure, mechanism and inhibitory propensity have been reviewed (Kapoor et al. 2018). Y6, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance (Zhao et al. 2018). ABCG2 confers resistance to several cancer treatments. Photodynamic therapy (PDT) is an anti-cancer method involving the use of light-activated photosensitisers to induce oxidative stress and cell death in cancers, but ABCG2 can efflux photosensitisers (Khot et al. 2019). Regorafenib sensitized MDR colon cancer cells to BCRP substrates by increasing  intracellular accumulation without changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Regorafenib stimulates BCRP ATPase activity and promotes a stable interaction between regorafenib and the transmembrane domain of BCRP (Zhang et al. 2019). Several potent inhibitors, effective in the millimicromolar range have been identified (Zou et al. 2020). Licochalcone A selectively resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs (Wu et al. 2020). The GXXXG motif promotes proper packing of the TMSs in the functional ABCG2 homodimer (Polgar et al. 2004). Molecular dynamics simulations have provided insight into the steps of the substrate transport process and its regulation by cholesterol (Nagy et al. 2020). Drug binding cavities other than the central binding site as well as a putative dynamic transport pathway for substrates with variable structures have been revealed. Membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion (Nagy et al. 2020).

Accession Number:Q9UNQ0
Protein Name:ATP-binding cassette sub-family G member 2
Molecular Weight:72314.00
Species: [9606]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate methotrexate, topoteca, flavopiridol, Heme, Glutathione, mitoxantrone, Urate, resveratrol, Hoechst 33342, pheophorbide a, folate, estradiol, cholesterol, progesterone, testosterone, tamoxife, miloxantrone, daunorubicin, doxorubicin, rhodamine123

Cross database links:

Genevestigator: Q9UNQ0
eggNOG: prNOG06758
DIP: DIP-29162N
RefSeq: NP_004818.2   
Entrez Gene ID: 9429   
Pfam: PF01061    PF00005   
OMIM: 603756  gene
KEGG: hsa:9429   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0005524 F:ATP binding
GO:0042803 F:protein homodimerization activity
GO:0008559 F:xenobiotic-transporting ATPase activity
GO:0042493 P:response to drug
GO:0006810 P:transport

References (17)

[1] “A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance.”  Allikmets   9850061
[2] “A multidrug resistance transporter from human MCF-7 breast cancer cells.”  Doyle   9861027
[3] “Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole structure.”  Komatani   11306452
[4] “The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.”  Zhou   11533706
[5] “The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.”  Zhang   12958161
[6] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota   14702039
[7] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project   15489334
[8] “Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes.”  Miyake   9892175
[9] “Role of ABCG1 and other ABCG family members in lipid metabolism.”  Schmitz   11590207
[10] “N-linked glycosylation of the human ABC transporter ABCG2 on asparagine 596 is not essential for expression, transport activity, or trafficking to the plasma membrane.”  Diop   15807535
[11] “Single amino acid (482) variants of the ABCG2 multidrug transporter: major differences in transport capacity and substrate recognition.”  Oezvegy-Laczka   15670731
[12] “Effect of Walker A mutation (K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2.”  Henriksen   15769853
[13] “Intramolecular disulfide bond is a critical check point determining degradative fates of ATP-binding cassette (ABC) transporter ABCG2 protein.”  Wakabayashi   17686774
[14] “Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8.”  Iida   12111378
[15] “Eight novel single nucleotide polymorphisms in ABCG2/BCRP in Japanese cancer patients administered irinotacan.”  Itoda   15618737
[16] “Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine.”  Zamber   12544509
[17] “Single nucleotide polymorphisms modify the transporter activity of ABCG2.”  Morisaki   15838659
5NJ3   5NJG   6ETI   6FEQ   6FFC   6HBU   6HCO   6HIJ   6HZM   6VXF   [...more]

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