Format

Send to

Choose Destination
Adv Cancer Res. 2015;125:71-96. doi: 10.1016/bs.acr.2014.10.003. Epub 2015 Jan 8.

Molecular basis of the polyspecificity of P-glycoprotein (ABCB1): recent biochemical and structural studies.

Author information

1
Center for Cancer Research, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
2
Center for Cancer Research, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: ambudkar@helix.nih.gov.

Abstract

ABCB1 (P-glycoprotein/P-gp) is an ATP-binding cassette transporter well known for its association with multidrug resistance in cancer cells. Powered by the hydrolysis of ATP, it effluxes structurally diverse compounds. In this chapter, we discuss current views on the molecular basis of the substrate polyspecificity of P-gp. One of the features that accounts for this property is the structural flexibility observed in P-gp. Several X-ray crystal structures of mouse P-gp have been published recently in the absence of nucleotide, with and without bound inhibitors. All the structures are in an inward-facing conformation exhibiting different degrees of domain separation, thus revealing a highly flexible protein. Biochemical and biophysical studies also demonstrate this flexibility in mouse as well as human P-gp. Site-directed mutagenesis has revealed the existence of multiple transport-active binding sites in P-gp for a single substrate. Thus, drugs can bind at either primary or secondary sites. Biochemical, molecular modeling, and structure-activity relationship studies suggest a large, common drug-binding pocket with overlapping sites for different substrates. We propose that in addition to the structural flexibility, the molecular or chemical flexibility also contributes to the binding of substrates to multiple sites forming the basis of polyspecificity.

KEYWORDS:

ABC transporter; Drug-binding sites; Multidrug resistance; P-glycoprotein; Polyspecificity; Structural flexibility

PMID:
25640267
DOI:
10.1016/bs.acr.2014.10.003
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center