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| Article Authors: | J M van Den Elsen; D A Kuntz; F J Hoedemaeker; D R Rose |
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| Article Title: | Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein. |
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| Reference ID: | 1014157 |
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| Abstract: | The ABC transporter, P-glycoprotein, is an integral membrane protein that mediates the ATP-driven efflux of drugs from multidrug-resistant cancer and HIV-infected cells. Anti-P-glycoprotein antibody C219 binds to both of the ATP-binding regions of P-glycoprotein and has been shown to inhibit its ATPase activity and drug binding capacity. C219 has been widely used in a clinical setting as a tumor marker, but recent observations of cross-reactivity with other proteins, including the c-erbB2 protein in breast cancer cells, impose potential limitations in detecting P-glycoprotein. We have determined the crystal structure at a resolution of 2.4 A of the variable fragment of C219 in complex with an epitope peptide derived from the nucleotide binding domain of P-glycoprotein. The 14-residue peptide adopts an amphipathic alpha-helical conformation, a secondary structure not previously observed in structures of antibody-peptide complexes. Together with available biochemical data, the crystal structure of the C219-peptide complex indicates the molecular basis of the cross-reactivity of C219 with non-multidrug resistance-associated proteins. Alignment of the C219 epitope with the recent crystal structure of the ATP-binding subunit of histidine permease suggests a structural basis for the inhibition of the ATP and drug binding capacity of P-glycoprotein by C219. The results provide a rationale for the development of C219 mutants with improved specificity and affinity that could be useful in antibody-based P-glycoprotein detection and therapy in multidrug resistant cancers. |
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| Affiliations: | Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto M5G 2M9, Ontario, Canada. |
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| Date: | 1999 |
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| Reference Type: | Literature |
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| PubMed ID: | 10570132 |
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| Journal: | Proc Natl Acad Sci U S A |
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| Journal Volume: | 96 |
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| Article Pages: | 13679-84 |
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| Journal ISSN: | 0027-8424 |
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| Article Chemical List: | Antibodies, Monoclonal;Epitopes, B-Lymphocyte;Immunoglobulin Fragments;Ligands;P-Glycoprotein;immunoglobulin Fv |
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| Article MeSH List: | Amino Acid Sequence; Antibodies, Monoclonal(chemistry; immunology); Crystallography, X-Ray; Epitopes, B-Lymphocyte(chemistry; immunology); Immunoglobulin Fragments(chemistry; immunology); Ligands; Models, Molecular; Molecular Sequence Data; P-Glycoprotein(chemistry; immunology); Protein Conformation |
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| Curation Last Updated: | 2013-05-28 21:39:01 |
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