2qq7

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[[Image:2qq7.png|left|200px]]
 
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{{STRUCTURE_2qq7| PDB=2qq7 | SCENE= }}
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==Crystal structure of drug resistant SRC kinase domain with irreversible inhibitor==
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<StructureSection load='2qq7' size='340' side='right'caption='[[2qq7]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2qq7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QQ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QQ7 FirstGlance]. <br>
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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]] 2.38&#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=SR2:(2E)-N-{4-[(3-BROMOPHENYL)AMINO]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUT-2-ENAMIDE'>SR2</scene></td></tr>
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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=2qq7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qq7 OCA], [https://pdbe.org/2qq7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qq7 RCSB], [https://www.ebi.ac.uk/pdbsum/2qq7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qq7 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/SRC_CHICK SRC_CHICK] Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates involved in this process. When cells adhere via focal adhesions to the extra-cellular matrix, signals are transmitted by integrins into the cell and result in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). Also active at the sites of cell-cell contact adherens junctions and at gap junctions. Implicated in the regulation of pre-mRNA-processing. Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus.<ref>PMID:1717492</ref> <ref>PMID:8550628</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/qq/2qq7_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2qq7 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Resistance to kinase-targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity.
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===Crystal structure of drug resistant SRC kinase domain with irreversible inhibitor===
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Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.,Michalczyk A, Kluter S, Rode HB, Simard JR, Grutter C, Rabiller M, Rauh D Bioorg Med Chem. 2008 Apr 1;16(7):3482-8. Epub 2008 Feb 20. PMID:18316192<ref>PMID:18316192</ref>
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{{ABSTRACT_PUBMED_18316192}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 2qq7" style="background-color:#fffaf0;"></div>
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[[2qq7]] is a 2 chain structure of [[Proto-oncogene tyrosine-protein kinase]] with sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QQ7 OCA].
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==See Also==
==See Also==
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*[[Proto-oncogene tyrosine-protein kinase|Proto-oncogene tyrosine-protein kinase]]
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*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:018316192</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Gallus gallus]]
[[Category: Gallus gallus]]
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[[Category: Non-specific protein-tyrosine kinase]]
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[[Category: Large Structures]]
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[[Category: Gruetter, C.]]
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[[Category: Gruetter C]]
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[[Category: Michalczyk, A.]]
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[[Category: Michalczyk A]]
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[[Category: Rauh, D.]]
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[[Category: Rauh D]]
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[[Category: Rode, H B.]]
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[[Category: Rode HB]]
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[[Category: Atp-binding]]
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[[Category: Drug resistance]]
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[[Category: Irreversible inhibitor]]
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[[Category: Lipoprotein]]
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[[Category: Myristate]]
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[[Category: Nucleotide-binding]]
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[[Category: Phosphorylation]]
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[[Category: Proto-oncogene]]
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[[Category: Sh2 domain]]
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[[Category: Sh3 domain]]
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[[Category: Src kinase domain]]
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[[Category: Transferase]]
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[[Category: Tyrosine-protein kinase]]
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Current revision

Crystal structure of drug resistant SRC kinase domain with irreversible inhibitor

PDB ID 2qq7

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