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3.A.1.201.1
Broad specificity multidrug resistance (MDR1; ABCB1; P-glycoprotein) efflux pump (exports organic cations and amphiphilic compounds of unrelated chemical structure) (These include: antibiotics, anti-viral agents, cancer chemotheraputic agents, hypertensives, depressants, histamines, emetics, and the protease inhibitor, lopinavir. Pgp also exports immunosuppressants, detergents, long-chain fatty acids, HIV protease inhibitors, synthetic tetramethylrosamine analogues, calcein M, etc.); peptide efflux pump; phospholipid (e.g., phosphatidyl serine), cholesterol and sterol flippase (also called ABCB1 and p-gp)). Binds and probably transports inhibitors and agonists of SUR (2.A.1.208.4) (Bessadok et al., 2011). The 3-d structure has been determined (Aller et al., 2009). It can pump from the cytoplasmic leaflet to either the outer leaflet or the outer medium (Katzir et al., 2010). The inhibitor, 5''-fluorosulfonylbenzoyl 5''-adenosine, an ATP analogue, interacts with both drug-substrate- and nucleotide-binding sites (Ohnuma et al., 2011). Inhibited by sildenafil (Shi et al., 2011), verapamil, indomethacin, probenecid, cetirizine (He et al. 2010), and lapatinib derivatives (Sodani et al., 2012), several of which are also substrates. HG-829 is a potent non-competitive inhibitor (Caceres et al., 2012).  Berberine, palmatine, jateorhizine, cetirizine and coptisine are all P-gp substrates, and cyclosporin A and verapamil are potent inhibitors (He et al. 2010; Zhang et al., 2011).  Transports clarithromycin (CAM), a macrolide antibiotic used to treat lung infections, more effectively than azithromycin (AZM) or telithromycin (TEL) (Togami et al. 2012).  Nucleotides, lipids and drugs bind synergistically to the pump (Marcoux et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  The centra cavity undergoes alternating access during ATP hydrolysis (van Wonderen et al. 2014).  Structure data suggest that signals are transduced through intracellular loops of the TMDs that slot into grooves on the NBDs. The Q loops at the base of these grooves are required to couple drug binding to the ATP catalytic cycle of drug export (Zolnerciks et al. 2014). Ocotillol analogues are strong competitive inhibitors (Zhang et al. 2015).  Durmus et al. 2015 have reviewed PGP transport of cancer chemotheraputic agents.  ABCB1 variants modulate therapeutic responses to modafinil and may partly explain pharmacoresistance in Narcolepse type 1 (NT1) patients (Moresco et al. 2016).  Inhibitors have been identified (Hemmer et al. 2015).  The open-and-close motion of the protein alters the surface topology of P-gp within the drug-binding pocket, explaning its polyspecificity (Esser et al. 2016). The ATP- and substrate-coupled conformational cycle of the mouse Pgp transporter have been defined showing that the energy released by ATP hydrolysis is harnessed in the NBDs in a two-stroke cycle (Verhalen et al. 2017).  Rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport (Reznicek et al. 2017).  It transports Huerzine A in the brain a drug that is used for the treatment of Alzheimer's disease (He et al. 2010; Zhang et al., 2011).  Transports clarithromycin (CAM), a macrolide antibiotic used to treat lung infections, more effectively than azithromycin (AZM) or telithromycin (TEL) (Togami et al. 2012).  Nucleotides, lipids and drugs bind synergistically to the pump (Marcoux et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  The centra cavity undergoes alternating access during ATP hydrolysis (van Wonderen et al. 2014).  Structure data suggest that signals are transduced through intracellular loops of the TMDs that slot into grooves on the NBDs. The Q loops at the base of these grooves are required to couple drug binding to the ATP catalytic cycle of drug export (Zolnerciks et al. 2014). Ocotillol analogues are strong competitive inhibitors (Zhang et al. 2015).  Durmus et al. 2015 have reviewed PGP transport of cancer chemotheraputic agents.  ABCB1 variants modulate therapeutic responses to modafinil and may partly explain pharmacoresistance in Narcolepse type 1 (NT1) patients (Moresco et al. 2016).  Inhibitors have been identified (Hemmer et al. 2015).  The open-and-close motion of the protein alters the surface topology of P-gp within the drug-binding pocket, explaning its polyspecificity (Esser et al. 2016). The ATP- and substrate-coupled conformational cycle of the mouse Pgp transporter have been defined showing that the energy released by ATP hydrolysis is harnessed in the NBDs in a two-stroke cycle (Verhalen et al. 2017).  Rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport (Reznicek et al. 2017).  It transports Huerzine A in the brain a drug that is used for the treatment of Alzheimer's disease (Li et al. 2017).

Accession Number:P08183
Protein Name:MDR1 aka PGY1 aka ABCB1
Length:1280
Molecular Weight:141479.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate protease inhibitors, long-chain fatty acids, anphiphilic compouds, organic cations, detergents, depressants, immunosuppressants, hypertensive drugs, emetics, Berberine, synthetic tetramethylrosamine analogues, sterols, anti-viral agents, lopinavir, calcein M, phospholipids, peptides, cancer chemotheraputic agents, antibiotics, histamines

Cross database links:

Genevestigator: P08183
HEGENOM: HBG758042
RefSeq: NP_000918.2   
Entrez Gene ID: 5243   
Pfam: PF00664    PF00005   
OMIM: 120080  phenotype
171050  gene
612244  phenotype
KEGG: hsa:5243   

Gene Ontology

GO:0009986 C:cell surface
GO:0016021 C:integral to membrane
GO:0005624 C:membrane fraction
GO:0005524 F:ATP binding
GO:0005515 F:protein binding
GO:0008559 F:xenobiotic-transporting ATPase activity
GO:0042493 P:response to drug
GO:0055085 P:transmembrane transport

References (19)

[1] “Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells.”  Chen C.-J.et.al.   2876781
[2] “Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins.”  Chen C.-J.et.al.   1967175
[3] “Multidrug-resistant human sarcoma cells with a mutant P-glycoprotein, altered phenotype, and resistance to cyclosporins.”  Chen G.et.al.   9038218
[4] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[5] “The DNA sequence of human chromosome 7.”  Hillier L.W.et.al.   12853948
[6] “mdr1/P-glycoprotein gene segments analyzed from various human leukemic cell lines exhibiting different multidrug resistance profiles.”  Gekeler V.et.al.   1972623
[7] “P-glycoprotein gene (MDR1) cDNA from human adrenal: normal P-glycoprotein carries Gly185 with an altered pattern of multidrug resistance.”  Kioka N.et.al.   2568832
[8] “ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2.”  Kerb R.et.al.   11258197
[9] “Cytoplasmic domains of the transporter associated with antigen processing and P-glycoprotein interact with subunits of the proteasome.”  Begley G.S.et.al.   15488952
[10] “An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene.”  Choi K.H.et.al.   2897240
[11] “Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors.”  Mickley L.A.et.al.   9473242
[12] “A new polymorphism (N21D) in the exon 2 of the human MDR1 gene encoding the P-glycoprotein.”  Decleves X.et.al.   10790226
[13] “Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.”  Hoffmeyer S.et.al.   10716719
[14] “Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.”  Cascorbi I.et.al.   11240981
[15] “Polymorphism of MDR1 gene in healthy Japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys).”  Honda T.et.al.   15618700
[16] “Twelve novel single nucleotide polymorphisms in ABCB1/MDR1 among Japanese patients with ventricular tachycardia who were administered amiodarone.”  Itoda M.et.al.   15618713
[17] “Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population.”  Saito S.et.al.   11829140
[18] “MDR1 Ala893 polymorphism is associated with inflammatory bowel disease.”  Brant S.R.et.al.   14610718
[19] “The consensus coding sequences of human breast and colorectal cancers.”  Sjoeblom T.et.al.   16959974

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FASTA formatted sequence
1:	MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII 
61:	HGAGLPLMML VFGEMTDIFA NAGNLEDLMS NITNRSDIND TGFFMNLEED MTRYAYYYSG 
121:	IGAGVLVAAY IQVSFWCLAA GRQIHKIRKQ FFHAIMRQEI GWFDVHDVGE LNTRLTDDVS 
181:	KINEGIGDKI GMFFQSMATF FTGFIVGFTR GWKLTLVILA ISPVLGLSAA VWAKILSSFT 
241:	DKELLAYAKA GAVAEEVLAA IRTVIAFGGQ KKELERYNKN LEEAKRIGIK KAITANISIG 
301:	AAFLLIYASY ALAFWYGTTL VLSGEYSIGQ VLTVFFSVLI GAFSVGQASP SIEAFANARG 
361:	AAYEIFKIID NKPSIDSYSK SGHKPDNIKG NLEFRNVHFS YPSRKEVKIL KGLNLKVQSG 
421:	QTVALVGNSG CGKSTTVQLM QRLYDPTEGM VSVDGQDIRT INVRFLREII GVVSQEPVLF 
481:	ATTIAENIRY GRENVTMDEI EKAVKEANAY DFIMKLPHKF DTLVGERGAQ LSGGQKQRIA 
541:	IARALVRNPK ILLLDEATSA LDTESEAVVQ VALDKARKGR TTIVIAHRLS TVRNADVIAG 
601:	FDDGVIVEKG NHDELMKEKG IYFKLVTMQT AGNEVELENA ADESKSEIDA LEMSSNDSRS 
661:	SLIRKRSTRR SVRGSQAQDR KLSTKEALDE SIPPVSFWRI MKLNLTEWPY FVVGVFCAII 
721:	NGGLQPAFAI IFSKIIGVFT RIDDPETKRQ NSNLFSLLFL ALGIISFITF FLQGFTFGKA 
781:	GEILTKRLRY MVFRSMLRQD VSWFDDPKNT TGALTTRLAN DAAQVKGAIG SRLAVITQNI 
841:	ANLGTGIIIS FIYGWQLTLL LLAIVPIIAI AGVVEMKMLS GQALKDKKEL EGSGKIATEA 
901:	IENFRTVVSL TQEQKFEHMY AQSLQVPYRN SLRKAHIFGI TFSFTQAMMY FSYAGCFRFG 
961:	AYLVAHKLMS FEDVLLVFSA VVFGAMAVGQ VSSFAPDYAK AKISAAHIIM IIEKTPLIDS 
1021:	YSTEGLMPNT LEGNVTFGEV VFNYPTRPDI PVLQGLSLEV KKGQTLALVG SSGCGKSTVV 
1081:	QLLERFYDPL AGKVLLDGKE IKRLNVQWLR AHLGIVSQEP ILFDCSIAEN IAYGDNSRVV 
1141:	SQEEIVRAAK EANIHAFIES LPNKYSTKVG DKGTQLSGGQ KQRIAIARAL VRQPHILLLD 
1201:	EATSALDTES EKVVQEALDK AREGRTCIVI AHRLSTIQNA DLIVVFQNGR VKEHGTHQQL 
1261:	LAQKGIYFSM VSVQAGTKRQ