2d1x

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(New page: 200px<br /> <applet load="2d1x" size="450" color="white" frame="true" align="right" spinBox="true" caption="2d1x, resolution 1.90&Aring;" /> '''The crystal structu...)
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[[Image:2d1x.gif|left|200px]]<br />
 
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<applet load="2d1x" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2d1x, resolution 1.90&Aring;" />
 
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'''The crystal structure of the cortactin-SH3 domain and AMAP1-peptide complex'''<br />
 
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==Overview==
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==The crystal structure of the cortactin-SH3 domain and AMAP1-peptide complex==
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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.
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<StructureSection load='2d1x' size='340' side='right'caption='[[2d1x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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==About this Structure==
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<table><tr><td colspan='2'>[[2d1x]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D1X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2D1X FirstGlance]. <br>
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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].
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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==Reference==
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2d1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2d1x OCA], [https://pdbe.org/2d1x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2d1x RCSB], [https://www.ebi.ac.uk/pdbsum/2d1x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2d1x ProSAT]</span></td></tr>
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Targeting AMAP1 and cortactin binding bearing an atypical src homology 3/proline interface for prevention of breast cancer invasion and metastasis., Hashimoto S, Hirose M, Hashimoto A, Morishige M, Yamada A, Hosaka H, Akagi K, Ogawa E, Oneyama C, Agatsuma T, Okada M, Kobayashi H, Wada H, Nakano H, Ikegami T, Nakagawa A, Sabe H, Proc Natl Acad Sci U S A. 2006 May 2;103(18):7036-41. Epub 2006 Apr 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16636290 16636290]
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/SRC8_HUMAN SRC8_HUMAN] Contributes to the organization of the actin cytoskeleton and cell structure. Plays a role in the regulation of cell migration. Plays a role in the invasiveness of cancer cells, and the formation of metastases.<ref>PMID:21296879</ref> <ref>PMID:16636290</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d1/2d1x_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2d1x ConSurf].
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<div style="clear:both"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Agatsuma, T.]]
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[[Category: Agatsuma T]]
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[[Category: Akagi, K.]]
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[[Category: Akagi K]]
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[[Category: Hashimoto, A.]]
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[[Category: Hashimoto A]]
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[[Category: Hashimoto, S.]]
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[[Category: Hashimoto S]]
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[[Category: Hirose, M.]]
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[[Category: Hirose M]]
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[[Category: Hosaka, H.]]
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[[Category: Hosaka H]]
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[[Category: Ikegami, T.]]
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[[Category: Ikegami T]]
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[[Category: Kobayashi, H.]]
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[[Category: Kobayashi H]]
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[[Category: Morishige, M.]]
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[[Category: Morishige M]]
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[[Category: Nakagawa, A.]]
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[[Category: Nakagawa A]]
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[[Category: Nakano, H.]]
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[[Category: Nakano H]]
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[[Category: Ogawa, E.]]
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[[Category: Ogawa E]]
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[[Category: Okada, M.]]
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[[Category: Okada M]]
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[[Category: Oneyama, C.]]
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[[Category: Oneyama C]]
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[[Category: Sabe, H.]]
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[[Category: Sabe H]]
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[[Category: Wada, H.]]
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[[Category: Wada H]]
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[[Category: Yamada, A.]]
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[[Category: Yamada A]]
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[[Category: SO4]]
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[[Category: complex]]
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[[Category: proline-rich]]
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[[Category: sh3]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:25:33 2007''
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Current revision

The crystal structure of the cortactin-SH3 domain and AMAP1-peptide complex

PDB ID 2d1x

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