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| ==c-Src kinase domain in complex with small molecule inhibitor== | | ==c-Src kinase domain in complex with small molecule inhibitor== |
- | <StructureSection load='3f6x' size='340' side='right' caption='[[3f6x]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='3f6x' size='340' side='right'caption='[[3f6x]], [[Resolution|resolution]] 2.35Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[3f6x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Chick Chick]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3F6X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3F6X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3f6x]] is a 4 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=3F6X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3F6X FirstGlance]. <br> |
- | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IHH:[4-({4-[(5-CYCLOPROPYL-1H-PYRAZOL-3-YL)AMINO]QUINAZOLIN-2-YL}AMINO)PHENYL]ACETONITRILE'>IHH</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> |
- | <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 CHICK])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IHH:[4-({4-[(5-CYCLOPROPYL-1H-PYRAZOL-3-YL)AMINO]QUINAZOLIN-2-YL}AMINO)PHENYL]ACETONITRILE'>IHH</scene></td></tr> |
- | <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>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3f6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f6x OCA], [https://pdbe.org/3f6x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3f6x RCSB], [https://www.ebi.ac.uk/pdbsum/3f6x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3f6x ProSAT]</span></td></tr> |
- | <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=3f6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f6x OCA], [http://pdbe.org/3f6x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3f6x RCSB], [http://www.ebi.ac.uk/pdbsum/3f6x PDBsum]</span></td></tr> | + | |
| </table> | | </table> |
| == Function == | | == Function == |
- | [[http://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> | + | [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> |
| == Evolutionary Conservation == | | == Evolutionary Conservation == |
| [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Check<jmol> | | Check<jmol> |
| <jmolCheckbox> | | <jmolCheckbox> |
- | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f6/3f6x_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f6/3f6x_consurf.spt"</scriptWhenChecked> |
| <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| ==See Also== | | ==See Also== |
- | *[[Tyrosine kinase|Tyrosine kinase]] | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
- | [[Category: Chick]] | + | [[Category: Gallus gallus]] |
- | [[Category: Non-specific protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
- | [[Category: Kuriyan, J]] | + | [[Category: Kuriyan J]] |
- | [[Category: Maly, D J]] | + | [[Category: Maly DJ]] |
- | [[Category: Patrick, P Z]] | + | [[Category: Patrick PZ]] |
- | [[Category: Seeliger, M A]] | + | [[Category: Seeliger MA]] |
- | [[Category: Shokat, K M]] | + | [[Category: Shokat KM]] |
- | [[Category: Statsuk, A V]] | + | [[Category: Statsuk AV]] |
- | [[Category: Atp-binding]]
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- | [[Category: Kinase]]
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- | [[Category: Lipoprotein]]
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- | [[Category: Myristate]]
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- | [[Category: Nucleotide-binding]]
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- | [[Category: Phosphoprotein]]
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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: Transferase]]
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- | [[Category: Tyrosine-protein kinase]]
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| Structural highlights
Function
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.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The upstream protein kinases responsible for thousands of phosphorylation events in the phosphoproteome remain to be discovered. We developed a three-component chemical reaction which converts the transient noncovalent substrate-kinase complex into a covalently cross-linked product by utilizing a dialdehyde-based cross-linker, 1. Unfortunately, the reaction of 1 with a lysine in the kinase active site and an engineered cysteine on the substrate to form an isoindole cross-linked product could not be performed in the presence of competing cellular proteins due to nonspecific side reactions. In order to more selectively target the cross-linker to protein kinases in cell lysates, we replaced the weak, kinase-binding adenosine moiety of 1 with a potent protein kinase inhibitor scaffold. In addition, we replaced the o-phthaldialdehyde moiety in 1 with a less-reactive thiophene-2,3-dicarboxaldehyde moiety. The combination of these two structural modifications provides for cross-linking of a cysteine-containing substrate to its corresponding kinase in the presence of competing cellular proteins.
Tuning a three-component reaction for trapping kinase substrate complexes.,Statsuk AV, Maly DJ, Seeliger MA, Fabian MA, Biggs WH 3rd, Lockhart DJ, Zarrinkar PP, Kuriyan J, Shokat KM J Am Chem Soc. 2008 Dec 24;130(51):17568-74. PMID:19053485[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kremer NE, D'Arcangelo G, Thomas SM, DeMarco M, Brugge JS, Halegoua S. Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J Cell Biol. 1991 Nov;115(3):809-19. PMID:1717492
- ↑ Simonson MS, Wang Y, Herman WH. Nuclear signaling by endothelin-1 requires Src protein-tyrosine kinases. J Biol Chem. 1996 Jan 5;271(1):77-82. PMID:8550628
- ↑ Statsuk AV, Maly DJ, Seeliger MA, Fabian MA, Biggs WH 3rd, Lockhart DJ, Zarrinkar PP, Kuriyan J, Shokat KM. Tuning a three-component reaction for trapping kinase substrate complexes. J Am Chem Soc. 2008 Dec 24;130(51):17568-74. PMID:19053485 doi:10.1021/ja807066f
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