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3.A.1.208.8
Drug resistance pump; ABCC1 (MRP1), exports chemotherapeutic agents, organic anions such as leukotriene C4 (LTC4), 17-β-estradiol 17-β-D-glucuronide, glucuronide-X (E217βG, etoposide-glucuronide), estrone-3-sulfate, folic acid and methotrexate, arsenic triglutathione, arsenic and antimonial oxyanions, glutathione (GSH), GSSG, glutathione conjugates (GSH-X; LTC4, DNP-SG, EA-SG, NEH-SG), sulfate-X (E1S, DHEAS), HIV protease inhibitors, anthracyclines, epipodophyllotoxins, and Vinca alkaloids. Changing charged residues in TMS6 (K332, H335 and D336) gave rise to specific changes in specificity (Chen et al., 2006; Haimeur et al., 2002; Leslie et al., 2004).  Also, mutations in TMS 10 alter substrate binding and export of drugs (Zhang et al. 2006). MDR1 also exports cobalamine (Vitamin B12) (Beedholm-Ebsen et al., 2010) and cytotoxic metals including antimony, mercuric ions, arsenate and arsenite, but not copper, chromium, cobalt and aluminum, often as glutathione conjugates (Aleo et al., 2005; Vernhet et al., 2000). Notch1 regulates the expression in cultured cancer cells (Cho et al., 2011).  Structural and functional properties of MRP1 have been reviewed comprehensively (He et al. 2011).  Fluorescent substrates have been identified (Strouse et al. 2013).  It pumps out sulfur mustards and nitrogen mustards (mechlorethamine, HN2), potent vesicants developed as chemical warfare agents (Udasin et al. 2015). It has 3 membrane domains with a total of 17 TMSs. Loss of the aromatic side chain at position 583 impairs the release of ADP and thus effectively locks the transporter in a low-affinity solute binding state (Weigl et al. 2018). MRP1 Tyr1189 and Tyr1190, unlike the corresponding residues in SUR1, are not involved in its differential sensitivity to sulfonylureas, but nevertheless, may be involved in the transport activity of MRP1, especially with respect to glutathione, GSH (Conseil et al. 2005). Modulators of MRP1 activity have been found (Möhle et al. 2020). Glu1204 serves a dual role in membrane expression of MRP1 and in a step in its catalytic cycle subsequent to initial substrate binding (Situ et al. 2004). The cotransport mechanism of GSH with anticancer drugs by MRP1 has been examined (Zhao et al. 2020). The first cytoplasmic loop in the core structure of ABCC1 contains multiple amino acids essential for Its expression (Conseil and Cole 2021). Carboplatin, paclitaxel and topotecan bind specifically to Asn510 in transmembrane domain 1 of MRP1 (Haque et al. 2022). The farnesyl protein transferase inhibitor, lonafarnib (SCH66336), is an inhibitor of multidrug resistance proteins 1 and 2, Mrp1 and Mrp2 (Wang and Johnson 2003). A macrocyclic peptide, named CPI1, inhibits MRP1 with nanomolar potency but shows minimal inhibition of P-glycoprotein. A cryo-EM structure at 3.27 Å resolution shows that CPI1 binds MRP1 at the same location as the physiological substrate leukotriene C4 (LTC4). Residues that interact with both ligands contain large, flexible side chains that can form a variety of interactions, revealing how MRP1 recognizes multiple structurally unrelated molecules. CPI1 binding prevents the conformational changes necessary for ATP hydrolysis and substrate transport (Pietz et al. 2023). ABCB1 and ABCC1 function during the TGF-β-induced epithelial-mesenchymal transition, and the relationship between multidrug resistance and tumor progression has been considered (da Costa et al. 2023). The efflux of anti-psychotics through the blood-brain barrier (BBB) via this system has been demonstrated (Nasyrova et al. 2023). It is present in the intestine (Wang et al. 2024). Mrp1-mediated transport is modulated by the antiviral drug ritonavir in cultured primary astrocytes (Arend et al. 2024).ATP-binding cassette family C member 1, ABCC1, constrains metabolic responses to high-fat diet in male mice (Villalobos et al. 2024). Cryo-EM structures of ABCC1 revealed new conformational dynamics in the resting state (Zhang et al. 2024).  The multidrug resistance protein MRP1/ABCC1 provided protection against toxicity induced by arsenic and mercury (Ferdigg et al. 2025). The ABCC1 gene is expressed differentially in rat Alzhemier's Disease (Puris et al. 2022).

Accession Number:P33527
Protein Name:MRP1 aka ABCC1 aka MRP
Length:1531
Molecular Weight:171591.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:17
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate mercury(2+), arsenate(3-), arsenite(3-), glutathione, folic acid, methotrexate, leukotriene C4, glutathione conjugate, cobalamin, bis(2-chloroethyl) sulfide, antimony(0), estrone 3-sulfate, mechlorethamine

Cross database links:

RefSeq: NP_004987.2   
Entrez Gene ID: 4363   
Pfam: PF00664    PF00005   
OMIM: 158343  gene
KEGG: hsa:4363   

Gene Ontology

GO:0005887 C:integral to plasma membrane
GO:0005624 C:membrane fraction
GO:0005524 F:ATP binding
GO:0042626 F:ATPase activity, coupled to transmembrane m...
GO:0042493 P:response to drug
GO:0055085 P:transmembrane transport

References (27)

[1] “Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.”  Cole S.P.C.et.al.   1360704
[2] “Multidrug resistance-associated protein: sequence correction.”  Cole S.P.C.et.al.   8098549
[3] “Analysis of the intron-exon organization of the human multidrug-resistance protein gene (MRP) and alternative splicing of its mRNA.”  Grant C.E.et.al.   9344662
[4] “The sequence and analysis of duplication-rich human chromosome 16.”  Martin J.et.al.   15616553
[5] “Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q.”  Loftus B.J.et.al.   10493829
[6] “Membrane topology of the multidrug resistance protein (MRP). A study of glycosylation-site mutants reveals an extracytosolic NH2 terminus.”  Hipfner D.R.et.al.   9295302
[7] “Topology mapping of the amino-terminal half of multidrug resistance-associated protein by epitope insertion and immunofluorescence.”  Kast C.et.al.   9334225
[8] “Epitope insertion favors a six transmembrane domain model for the carboxy-terminal portion of the multidrug resistance-associated protein.”  Kast C.et.al.   9485377
[9] “Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1.”  Sjoelinder M.et.al.   10064732
[10] “The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes.”  Robbiani D.F.et.al.   11114332
[11] “Mutations of the Walker B motif in the first nucleotide binding domain of multidrug resistance protein MRP1 prevent conformational maturation.”  Cui L.et.al.   11469806
[12] “Mutation of a single conserved tryptophan in multidrug resistance protein 1 (MRP1/ABCC1) results in loss of drug resistance and selective loss of organic anion transport.”  Ito K.et.al.   11278867
[13] “Identification of an amino acid residue in multidrug resistance protein 1 critical for conferring resistance to anthracyclines.”  Zhang D.-W.et.al.   11278596
[14] “Mutational analysis of ionizable residues proximal to the cytoplasmic interface of membrane spanning domain 3 of the multidrug resistance protein, MRP1 (ABCC1): glutamate 1204 is important for both the expression and catalytic activity of the transporter.”  Situ D.et.al.   15208328
[15] “Transmembrane helix 11 of multidrug resistance protein 1 (MRP1/ABCC1): identification of polar amino acids important for substrate specificity and binding of ATP at nucleotide binding domain 1.”  Zhang D.-W.et.al.   15260484
[16] “Functional importance of three basic residues clustered at the cytosolic interface of transmembrane helix 15 in the multidrug and organic anion transporter MRP1 (ABCC1).”  Conseil G.et.al.   16230346
[17] “Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.”  Daub H.et.al.   18691976
[18] “Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.”  Gauci S.et.al.   19413330
[19] “Large-scale proteomics analysis of the human kinome.”  Oppermann F.S.et.al.   19369195
[20] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[21] “Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site.”  Ramaen O.et.al.   16697012
[22] “Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.”  Le Saux O.et.al.   10835642
[23] “Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.”  Ringpfeil F.et.al.   10811882
[24] “Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution.”  Conrad S.et.al.   11721885
[25] “Identification of novel polymorphisms in the pM5 and MRP1 (ABCC1) genes at locus 16p13.1 and exclusion of both genes as responsible for pseudoxanthoma elasticum.”  Perdu J.et.al.   11139250
[26] “Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects.”  Ito S.et.al.   11266082
[27] “DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.”  Ley T.J.et.al.   18987736
Structure:
2CBZ   4C3Z     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MALRGFCSAD GSDPLWDWNV TWNTSNPDFT KCFQNTVLVW VPCFYLWACF PFYFLYLSRH 
61:	DRGYIQMTPL NKTKTALGFL LWIVCWADLF YSFWERSRGI FLAPVFLVSP TLLGITMLLA 
121:	TFLIQLERRK GVQSSGIMLT FWLVALVCAL AILRSKIMTA LKEDAQVDLF RDITFYVYFS 
181:	LLLIQLVLSC FSDRSPLFSE TIHDPNPCPE SSASFLSRIT FWWITGLIVR GYRQPLEGSD 
241:	LWSLNKEDTS EQVVPVLVKN WKKECAKTRK QPVKVVYSSK DPAQPKESSK VDANEEVEAL 
301:	IVKSPQKEWN PSLFKVLYKT FGPYFLMSFF FKAIHDLMMF SGPQILKLLI KFVNDTKAPD 
361:	WQGYFYTVLL FVTACLQTLV LHQYFHICFV SGMRIKTAVI GAVYRKALVI TNSARKSSTV 
421:	GEIVNLMSVD AQRFMDLATY INMIWSAPLQ VILALYLLWL NLGPSVLAGV AVMVLMVPVN 
481:	AVMAMKTKTY QVAHMKSKDN RIKLMNEILN GIKVLKLYAW ELAFKDKVLA IRQEELKVLK 
541:	KSAYLSAVGT FTWVCTPFLV ALCTFAVYVT IDENNILDAQ TAFVSLALFN ILRFPLNILP 
601:	MVISSIVQAS VSLKRLRIFL SHEELEPDSI ERRPVKDGGG TNSITVRNAT FTWARSDPPT 
661:	LNGITFSIPE GALVAVVGQV GCGKSSLLSA LLAEMDKVEG HVAIKGSVAY VPQQAWIQND 
721:	SLRENILFGC QLEEPYYRSV IQACALLPDL EILPSGDRTE IGEKGVNLSG GQKQRVSLAR 
781:	AVYSNADIYL FDDPLSAVDA HVGKHIFENV IGPKGMLKNK TRILVTHSMS YLPQVDVIIV 
841:	MSGGKISEMG SYQELLARDG AFAEFLRTYA STEQEQDAEE NGVTGVSGPG KEAKQMENGM 
901:	LVTDSAGKQL QRQLSSSSSY SGDISRHHNS TAELQKAEAK KEETWKLMEA DKAQTGQVKL 
961:	SVYWDYMKAI GLFISFLSIF LFMCNHVSAL ASNYWLSLWT DDPIVNGTQE HTKVRLSVYG 
1021:	ALGISQGIAV FGYSMAVSIG GILASRCLHV DLLHSILRSP MSFFERTPSG NLVNRFSKEL 
1081:	DTVDSMIPEV IKMFMGSLFN VIGACIVILL ATPIAAIIIP PLGLIYFFVQ RFYVASSRQL 
1141:	KRLESVSRSP VYSHFNETLL GVSVIRAFEE QERFIHQSDL KVDENQKAYY PSIVANRWLA 
1201:	VRLECVGNCI VLFAALFAVI SRHSLSAGLV GLSVSYSLQV TTYLNWLVRM SSEMETNIVA 
1261:	VERLKEYSET EKEAPWQIQE TAPPSSWPQV GRVEFRNYCL RYREDLDFVL RHINVTINGG 
1321:	EKVGIVGRTG AGKSSLTLGL FRINESAEGE IIIDGINIAK IGLHDLRFKI TIIPQDPVLF 
1381:	SGSLRMNLDP FSQYSDEEVW TSLELAHLKD FVSALPDKLD HECAEGGENL SVGQRQLVCL 
1441:	ARALLRKTKI LVLDEATAAV DLETDDLIQS TIRTQFEDCT VLTIAHRLNT IMDYTRVIVL 
1501:	DKGEIQEYGA PSDLLQQRGL FYSMAKDAGL V