ATP-binding cassette, sub-family B (MDR/TAP), member 1
Crystallographic structure of the mouse MDR3 protein. The approximate positioning of the protein in the cell membrane is indicated by the blue (extracellular face) and red (cytoplasmic face) lines. The protein is depicted as a rainbow colored cartoon (N-terminus = blue, C-terminus = red). A cyclic peptide inhibitor QZ59 is represented by a space-filling model.
Available structures PDB , , Identifiers Symbols External IDs GeneCards: Gene Ontology Molecular function •
Cellular component •
Biological process •
Sources: Amigo / QuickGO RNA expression pattern Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) PubMed searchABCB1 at EBI Gene Expression Atlas ABCB1 is differentially expressed in 97 experiments [93 up/106 dn]: 26 organism parts: kidney [2 up/0 dn], bone marrow [0 up/2 dn], ...; 29 disease states: normal [10 up/3 dn], glioblastoma [0 up/2 dn], ...; 30 cell types, 22 cell lines, 11 compound treatments and 16 other conditions. Factor Value Factor Up/Down Legend: - number of studies the gene is up/down in Normal Disease state 10/3 None Compound treatment 3/0 Stromal cell Cell type 1/2 Kidney Cell type 2/0 MDA-MB-231 Cell line 0/2 Glioblastoma Disease state 0/2 Epithelial cell Cell type 0/2 HeLa Cell line 0/2 Primary Disease staging 2/0 Bone marrow Organism part 0/2 ABCB1 expression data in ATLAS
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is a glycoprotein that in humans is encoded by the ABCB1 gene. P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR/TAP subfamily.
Pgp is extensively distributed and expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, adrenal gland and capillary endothelial cells comprising the blood-brain and blood-testis barrier.
The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier.
ABCB1 is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a defense mechanism against harmful substances.
ABCB1 transports various substrates across the cell membrane including:
- Drugs such as colchicine, tacrolimus and quinidine
- Chemotherapeutic agents such as etoposide, doxorubicin, and vinblastine
- Cardiac glycosides like digoxin
- Immunosuppressive agents
- Glucocorticoids like dexamethasone
- HIV-type 1 antiretroviral therapy agents like protease inhibitors and nonnucleoside reverse transcriptase inhibitors.
Its ability to transport the above substrates accounts for the many roles of ABCB1 including:
- Regulating the distribution and bioavailability of drugs
- Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, and therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
- Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs
- The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen
- The transport of compounds out of the brain across the blood-brain barrier
- Digoxin uptake
- Prevention of ivermectin entry into the central nervous system
- The migration of dendritic cells
- Protection of hematopoietic stem cells from toxins.
Pgp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal glycosylation. The N-term half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with 6 transmembrane domains and an ATP-binding site that shows over 65% of amino acid similarity with the first half of the polypeptide. In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U). The structure was derived from the mouse MDR3 gene product heterologously expressed in Pichia pastoris yeast. The structure of mouse P-gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X)Ward A, Reyes CL, Yu J, Roth CB, Chang G (November 2007). "Flexibility in the ABC transporter MsbA: Alternating access with a twist". Proc. Natl. Acad. Sci. U.S.A. 104 (48): 19005–10. doi:10.1073/pnas.0709388104. PMC 2141898. PMID 18024585. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2141898. that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P-gp is lined with aromatic amino acid side chains.
Mechanism of action
Binding of a substrate and ATP molecule occur simulatenously. Following binding of each, ATP hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets the protein.
P-glycoprotein is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.
Detecting the activity of the transporter
The activity of the transporter can be determined by both membrane ATPase and cellular calcein assays.
The ABCB1 Transporter is also used to differentiate Transitional B-cells from Naive B-cells. Dyes such as Rhodamine123 and MitoTracker Dyes from Invitrogen can be used to make this differentiation.Wirths S, Lanzavecchia A (December 2005). "ABCB1 transporter discriminates human resting naive B cells from cycling transitional and memory B cells". Eur. J. Immunol. 35 (12): 3433–41. doi:10.1002/eji.200535364. PMID 16259010.
- MDR1 defect
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- MeSH P-Glycoprotein
- Jessica R Oesterheld (2002-05-01). "P-glycoprotein". Mental Health Connections, Inc. Archived from the original on 2008-02-07. http://web.archive.org/web/20080207233027/http://www.mhc.com/PGP/PgpMain.HTML. Retrieved 2008-03-02.
- P-glycoprotein substrate prediction
A B C D E F G see also ABC transporter disorders
B memb: cead, trns (1A, 1C, 1F, 2A, 3A1, 3A2-3, 3D), othr
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