3qlg

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==Crystal structure of the L317I mutant of the C-src tyrosine kinase domain complexed with dasatinib==
==Crystal structure of the L317I mutant of the C-src tyrosine kinase domain complexed with dasatinib==
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<StructureSection load='3qlg' size='340' side='right' caption='[[3qlg]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
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<StructureSection load='3qlg' size='340' side='right'caption='[[3qlg]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3qlg]] is a 2 chain structure 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=3QLG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QLG FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3qlg]] 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=3QLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QLG FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1N1:N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE'>1N1</scene></td></tr>
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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]] 2.75&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3of0|3of0]], [[3oez|3oez]], [[3qlf|3qlf]], [[3g5d|3g5d]]</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=1N1:N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE'>1N1</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SRC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9031 Gallus gallus])</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=3qlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlg OCA], [https://pdbe.org/3qlg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qlg RCSB], [https://www.ebi.ac.uk/pdbsum/3qlg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlg ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlg RCSB], [http://www.ebi.ac.uk/pdbsum/3qlg PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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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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The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. Imatinib is less effective against c-Src, which is difficult to understand because residues interacting with imatinib in crystal structures of Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase domain in complex with imatinib closely resembles that of Abl*imatinib and c-Kit*imatinib, and differs significantly from the inactive "Src/CDK" conformation of the Src family kinases. Attempts to increase the affinity of c-Src for imatinib by swapping residues with the corresponding residues in Abl have not been successful, suggesting that the thermodynamic penalty for adoption of the imatinib-binding conformation by c-Src is distributed over a broad region of the structure. Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding.
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c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty.,Seeliger MA, Nagar B, Frank F, Cao X, Henderson MN, Kuriyan J Structure. 2007 Mar;15(3):299-311. PMID:17355866<ref>PMID:17355866</ref>
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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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==See Also==
==See Also==
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*[[Tyrosine kinase|Tyrosine kinase]]
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*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</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: Boubeva, R]]
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[[Category: Boubeva R]]
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[[Category: Pernot, L]]
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[[Category: Pernot L]]
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[[Category: Perozzo, R]]
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[[Category: Perozzo R]]
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[[Category: Scapozza, L]]
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[[Category: Scapozza L]]
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[[Category: C-src l317i mutant]]
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[[Category: Dasatinib]]
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[[Category: Transferase]]
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[[Category: Tyrosine kinase]]
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Current revision

Crystal structure of the L317I mutant of the C-src tyrosine kinase domain complexed with dasatinib

PDB ID 3qlg

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