2ap2
From Proteopedia
(New page: 200px<br /> <applet load="2ap2" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ap2, resolution 2.4Å" /> '''SINGLE CHAIN FV OF C...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2ap2.gif|left|200px]]<br /> | + | [[Image:2ap2.gif|left|200px]]<br /><applet load="2ap2" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2ap2" size=" | + | |
caption="2ap2, resolution 2.4Å" /> | caption="2ap2, resolution 2.4Å" /> | ||
'''SINGLE CHAIN FV OF C219 IN COMPLEX WITH SYNTHETIC EPITOPE PEPTIDE'''<br /> | '''SINGLE CHAIN FV OF C219 IN COMPLEX WITH SYNTHETIC EPITOPE PEPTIDE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The ABC transporter, P-glycoprotein, is an integral membrane protein that | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2AP2 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http:// | + | 2AP2 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AP2 OCA]. |
==Reference== | ==Reference== | ||
| Line 14: | Line 13: | ||
[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Elsen, J | + | [[Category: Elsen, J M.H Van Den.]] |
| - | [[Category: Rose, D | + | [[Category: Rose, D R.]] |
[[Category: c219]] | [[Category: c219]] | ||
[[Category: immunoglobulin]] | [[Category: immunoglobulin]] | ||
| Line 22: | Line 21: | ||
[[Category: single chain fv]] | [[Category: single chain fv]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:31 2008'' |
Revision as of 14:29, 21 February 2008
|
SINGLE CHAIN FV OF C219 IN COMPLEX WITH SYNTHETIC EPITOPE PEPTIDE
Overview
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.
About this Structure
2AP2 is a Protein complex structure of sequences from Mus musculus. Full crystallographic information is available from OCA.
Reference
Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein., van Den Elsen JM, Kuntz DA, Hoedemaeker FJ, Rose DR, Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13679-84. PMID:10570132
Page seeded by OCA on Thu Feb 21 16:29:31 2008
