2d1x: Difference between revisions

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[[Image:2d1x.gif|left|200px]]<br />

[[Image:2d1x.gif|left|200px]]<br /><applet load="2d1x" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="2d1x" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="2d1x, resolution 1.90Å" />

'''The crystal structure of the cortactin-SH3 domain and AMAP1-peptide complex'''<br />

==Overview==

Invasive potentials of carcinomas greatly contribute to their metastasis, which is a major threat in most cancers. We have recently shown that Arf6, plays a pivotal role in breast cancer invasive activities and identified, AMAP1 as an effector of GTP-Arf6 in invasion. Expression of AMAP1, correlates well with invasive phenotypes of primary tumors of the human, breast. We also have shown that AMAP1 functions by forming a trimeric, protein complex with cortactin and paxillin. In this complex, AMAP1 binds, to the src homology 3 (SH3) domain of cortactin via its proline-rich, peptide, SKKRPPPPPPGHKRT. SH3 domains are known to bind generally to the, proline-rich ligands with a one-to-one stoichiometry. We found that, AMAP1/cortactin binding is very atypical in its stoichiometry and, interface structure, in which one AMAP1 proline-rich peptide binds to two, cortactin SH3 domains simultaneously. We made a cell-permeable peptide, derived from the AMAP1 peptide, and we show that this peptide specifically, blocks AMAP1/cortactin binding, but not other canonical SH3/proline, bindings, and effectively inhibits breast cancer invasion and metastasis., Moreover, this peptide was found to block invasion of other types of, cancers, such as glioblastomas and lung carcinomas. We also found that a, small-molecule compound, UCS15A, which was previously judged as a weak, inhibitor against canonical SH3/proline bindings, effectively inhibits, AMAP1/cortactin binding and breast cancer invasion and metastasis., Together with fine structural analysis, we propose that the, AMAP1/cortactin complex, which is not detected in normal mammary, epithelial cells, is an excellent drug target for cancer therapeutics.

Invasive potentials of carcinomas greatly contribute to their metastasis, which is a major threat in most cancers. We have recently shown that Arf6 plays a pivotal role in breast cancer invasive activities and identified AMAP1 as an effector of GTP-Arf6 in invasion. Expression of AMAP1 correlates well with invasive phenotypes of primary tumors of the human breast. We also have shown that AMAP1 functions by forming a trimeric protein complex with cortactin and paxillin. In this complex, AMAP1 binds to the src homology 3 (SH3) domain of cortactin via its proline-rich peptide, SKKRPPPPPPGHKRT. SH3 domains are known to bind generally to the proline-rich ligands with a one-to-one stoichiometry. We found that AMAP1/cortactin binding is very atypical in its stoichiometry and interface structure, in which one AMAP1 proline-rich peptide binds to two cortactin SH3 domains simultaneously. We made a cell-permeable peptide derived from the AMAP1 peptide, and we show that this peptide specifically blocks AMAP1/cortactin binding, but not other canonical SH3/proline bindings, and effectively inhibits breast cancer invasion and metastasis. Moreover, this peptide was found to block invasion of other types of cancers, such as glioblastomas and lung carcinomas. We also found that a small-molecule compound, UCS15A, which was previously judged as a weak inhibitor against canonical SH3/proline bindings, effectively inhibits AMAP1/cortactin binding and breast cancer invasion and metastasis. Together with fine structural analysis, we propose that the AMAP1/cortactin complex, which is not detected in normal mammary epithelial cells, is an excellent drug target for cancer therapeutics.

==About this Structure==

2D1X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2D1X OCA].

2D1X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D1X OCA].

==Reference==

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[[Category: sh3]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12~~ 21:25:~~33 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:54:34 2008''

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@@ Line 1: / Line 1: @@
-[[Image:2d1x.gif|left|200px]]<br />
+[[Image:2d1x.gif|left|200px]]<br /><applet load="2d1x" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2d1x" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2d1x, resolution 1.90&Aring;" />
 '''The crystal structure of the cortactin-SH3 domain and AMAP1-peptide complex'''<br />
 ==Overview==
-Invasive potentials of carcinomas greatly contribute to their metastasis, which is a major threat in most cancers. We have recently shown that Arf6, plays a pivotal role in breast cancer invasive activities and identified, AMAP1 as an effector of GTP-Arf6 in invasion. Expression of AMAP1, correlates well with invasive phenotypes of primary tumors of the human, breast. We also have shown that AMAP1 functions by forming a trimeric, protein complex with cortactin and paxillin. In this complex, AMAP1 binds, to the src homology 3 (SH3) domain of cortactin via its proline-rich, peptide, SKKRPPPPPPGHKRT. SH3 domains are known to bind generally to the, proline-rich ligands with a one-to-one stoichiometry. We found that, AMAP1/cortactin binding is very atypical in its stoichiometry and, interface structure, in which one AMAP1 proline-rich peptide binds to two, cortactin SH3 domains simultaneously. We made a cell-permeable peptide, derived from the AMAP1 peptide, and we show that this peptide specifically, blocks AMAP1/cortactin binding, but not other canonical SH3/proline, bindings, and effectively inhibits breast cancer invasion and metastasis., Moreover, this peptide was found to block invasion of other types of, cancers, such as glioblastomas and lung carcinomas. We also found that a, small-molecule compound, UCS15A, which was previously judged as a weak, inhibitor against canonical SH3/proline bindings, effectively inhibits, AMAP1/cortactin binding and breast cancer invasion and metastasis., Together with fine structural analysis, we propose that the, AMAP1/cortactin complex, which is not detected in normal mammary, epithelial cells, is an excellent drug target for cancer therapeutics.
+Invasive potentials of carcinomas greatly contribute to their metastasis, which is a major threat in most cancers. We have recently shown that Arf6 plays a pivotal role in breast cancer invasive activities and identified AMAP1 as an effector of GTP-Arf6 in invasion. Expression of AMAP1 correlates well with invasive phenotypes of primary tumors of the human breast. We also have shown that AMAP1 functions by forming a trimeric protein complex with cortactin and paxillin. In this complex, AMAP1 binds to the src homology 3 (SH3) domain of cortactin via its proline-rich peptide, SKKRPPPPPPGHKRT. SH3 domains are known to bind generally to the proline-rich ligands with a one-to-one stoichiometry. We found that AMAP1/cortactin binding is very atypical in its stoichiometry and interface structure, in which one AMAP1 proline-rich peptide binds to two cortactin SH3 domains simultaneously. We made a cell-permeable peptide derived from the AMAP1 peptide, and we show that this peptide specifically blocks AMAP1/cortactin binding, but not other canonical SH3/proline bindings, and effectively inhibits breast cancer invasion and metastasis. Moreover, this peptide was found to block invasion of other types of cancers, such as glioblastomas and lung carcinomas. We also found that a small-molecule compound, UCS15A, which was previously judged as a weak inhibitor against canonical SH3/proline bindings, effectively inhibits AMAP1/cortactin binding and breast cancer invasion and metastasis. Together with fine structural analysis, we propose that the AMAP1/cortactin complex, which is not detected in normal mammary epithelial cells, is an excellent drug target for cancer therapeutics.
 ==About this Structure==
-D1X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2D1X OCA].
+D1X is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D1X OCA].
 ==Reference==
@@ Line 36: / Line 35: @@
 [[Category: sh3]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:25:33 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:54:34 2008''