2ap2: Difference between revisions

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[[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="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="2ap2, resolution 2.4Å" />

'''SINGLE CHAIN FV OF C219 IN COMPLEX WITH SYNTHETIC EPITOPE PEPTIDE'''<br />

==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.

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 [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://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2AP2 OCA].

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==

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[[Category: Mus musculus]]

[[Category: Protein complex]]

[[Category: Elsen, J.M.H.Van.Den.]]

[[Category: Elsen, J M.H Van Den.]]

[[Category: Rose, D.R.]]

[[Category: Rose, D R.]]

[[Category: c219]]

[[Category: immunoglobulin]]

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[[Category: single chain fv]]

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@@ 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="450" color="white" frame="true" align="right" spinBox="true"
 caption="2ap2, resolution 2.4&Aring;" />
 '''SINGLE CHAIN FV OF C219 IN COMPLEX WITH SYNTHETIC EPITOPE PEPTIDE'''<br />
 ==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.
+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==
-AP2 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2AP2 OCA].
+AP2 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==
@@ Line 14: / Line 13: @@
 [[Category: Mus musculus]]
 [[Category: Protein complex]]
-[[Category: Elsen, J.M.H.Van.Den.]]
+[[Category: Elsen, J M.H Van Den.]]
-[[Category: Rose, D.R.]]
+[[Category: Rose, D R.]]
 [[Category: c219]]
 [[Category: immunoglobulin]]
@@ Line 22: / Line 21: @@
 [[Category: single chain fv]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 18 09:47:31 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:31 2008''