Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2

ABCG2 confers resistance to cancer cells by mediating the ATP-dependent outward efflux of chemotherapeutic compounds. Recent studies have indicated that the protein contains a number of interconnected drug binding sites. The present investigation examines the coupling of drug binding to ATP hydrolys...

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Bibliographic Details
Published in:The FEBS journal 2008-09, Vol.275 (17), p.4354-4362
Main Authors: McDevitt, Christopher A, Crowley, Emily, Hobbs, Gemma, Starr, Kate J, Kerr, Ian D, Callaghan, Richard
Format: Article
Language:English
Subjects:
ABC transporter
Adenosine triphosphatase
Adenosine Triphosphate - metabolism
Animals
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacokinetics
ATP Binding Cassette Transporter, Sub-Family G, Member 2
ATP-Binding Cassette Transporters - physiology
Binding sites
Biochemistry
Cancer
Cell Line
Chemotherapy
Daunorubicin - metabolism
Daunorubicin - pharmacokinetics
Drug resistance
membrane protein
Moths
multidrug‐resistance
Neoplasm Proteins - physiology
power‐stroke
Protein Binding
Radioligand Assay
Tritium
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Summary:ABCG2 confers resistance to cancer cells by mediating the ATP-dependent outward efflux of chemotherapeutic compounds. Recent studies have indicated that the protein contains a number of interconnected drug binding sites. The present investigation examines the coupling of drug binding to ATP hydrolysis. Initial drug binding to the protein requires a high-affinity interaction with the drug binding site, followed by transition and reorientation to the low-affinity state to enable dissociation at the extracellular face. [³H]Daunomycin binding to the ABCG2R⁴⁸²G isoform was examined in the nucleotide-bound and post-hydrolytic conformations. Binding of [³H]daunomycin was displaced by ATP analogues, indicating transition to a low-affinity conformation prior to hydrolysis. The low-affinity state was observed to be retained immediately post-hydrolysis. Therefore, the dissociation of phosphate and/or ADP is likely to be responsible for resetting of the transporter. The data indicate that, like ABCB1 and ABCC1, the 'power stroke' for translocation in ABCG2R⁴⁸²G is the binding of nucleotide.
ISSN:1742-464X
1742-4658
DOI:10.1111/j.1742-4658.2008.06578.x