Epitopes described in "Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein."

Article Authors:J M van Den Elsen; D A Kuntz; F J Hoedemaeker; D R Rose
Article Title:Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein.
Reference Detail
Reference ID:1014157
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.
Affiliations:Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto M5G 2M9, Ontario, Canada.
Reference Type:Literature
PubMed ID:10570132
Journal:Proc Natl Acad Sci U S A
Journal Volume:96
Article Pages:13679-84
Journal ISSN:0027-8424
Article Chemical List:Antibodies, Monoclonal;Epitopes, B-Lymphocyte;Immunoglobulin Fragments;Ligands;P-Glycoprotein;immunoglobulin Fv
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
Curation Last Updated:2015-06-05 01:35:11