2AP2

SINGLE CHAIN FV OF C219 IN COMPLEX WITH SYNTHETIC EPITOPE PEPTIDE

Summary for 2AP2

• Entry DOI: 10.2210/pdb2ap2/pdb
• Descriptor: SINGLE CHAIN FV, P-GLYCOPROTEIN (3 entities in total)
• Functional Keywords: single chain fv, monoclonal antibody, c219, p-glycoprotein, immunoglobulin, immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 4
• Total formula weight: 61792.10

Authors

Van Den Elsen, J.M.H.,Rose, D.R. (deposition date: 1999-03-22, release date: 1999-11-24, Last modification date: 2024-10-16)

Primary citation

van Den Elsen, J.M.,Kuntz, D.A.,Hoedemaeker, F.J.,Rose, D.R.
Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein.
Proc.Natl.Acad.Sci.USA, 96:13679-13684, 1999

PubMed 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.

PubMed: 10570132
DOI: 10.1073/pnas.96.24.13679

Experimental method

X-RAY DIFFRACTION (2.4 Å)