Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1)

He, Shu-Ming, Li, Songshu, Kanwar, Jagat R. and Zhou, Shu-Feng 2011, Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1), Current medicinal chemistry, vol. 18, no. 3, pp. 439-481.

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Title Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1)
Author(s) He, Shu-Ming
Li, Songshu
Kanwar, Jagat R.
Zhou, Shu-Feng
Journal name Current medicinal chemistry
Volume number 18
Issue number 3
Start page 439
End page 481
Total pages 43
Publisher Bentham Science Publishers Ltd
Place of publication Bussum, Netherlands
Publication date 2011-01
ISSN 0929-8673
1875-533X
Keyword(s) MRP1
substrate
inhibitor
structure-activity relationship
homology model
mutation
Summary Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.
Language eng
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2011, Bentham Science Publishers
Persistent URL http://hdl.handle.net/10536/DRO/DU:30031502

Document type: Journal Article
Collection: Centre for Biotechnology and Interdisciplinary Sciences (BioDeakin)
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