|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Yes1-SH2 in complex with monobody Mb(Yes_1)== | | ==Yes1-SH2 in complex with monobody Mb(Yes_1)== |
| - | <StructureSection load='5mtj' size='340' side='right' caption='[[5mtj]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='5mtj' size='340' side='right'caption='[[5mtj]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mtj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MTJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MTJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mtj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MTJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.949Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5mtj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mtj OCA], [http://pdbe.org/5mtj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mtj RCSB], [http://www.ebi.ac.uk/pdbsum/5mtj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mtj ProSAT]</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=5mtj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mtj OCA], [https://pdbe.org/5mtj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mtj RCSB], [https://www.ebi.ac.uk/pdbsum/5mtj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mtj ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/YES_MOUSE YES_MOUSE]] Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGRF, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis (By similarity). | + | [https://www.uniprot.org/uniprot/YES_MOUSE YES_MOUSE] Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGRF, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 19: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 5mtj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5mtj" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Non-specific protein-tyrosine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hantschel, O]] | + | [[Category: Large Structures]] |
| - | [[Category: Koide, S]] | + | [[Category: Mus musculus]] |
| - | [[Category: Kukenshoner, T]] | + | [[Category: Hantschel O]] |
| - | [[Category: Sha, F]] | + | [[Category: Koide S]] |
| - | [[Category: Monobody]] | + | [[Category: Kukenshoner T]] |
| - | [[Category: Signaling]] | + | [[Category: Sha F]] |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Src homology]]
| + | |
| Structural highlights
Function
YES_MOUSE Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGRF, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis (By similarity).
Publication Abstract from PubMed
The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling, as well as to interfere with aberrant SFK signaling networks in cancer cells.
Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies.,Kukenshoner T, Schmit NE, Bouda E, Sha F, Pojer F, Koide A, Seeliger M, Koide S, Hantschel O J Mol Biol. 2017 Mar 24. pii: S0022-2836(17)30139-0. doi:, 10.1016/j.jmb.2017.03.023. PMID:28347651[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kukenshoner T, Schmit NE, Bouda E, Sha F, Pojer F, Koide A, Seeliger M, Koide S, Hantschel O. Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies. J Mol Biol. 2017 Mar 24. pii: S0022-2836(17)30139-0. doi:, 10.1016/j.jmb.2017.03.023. PMID:28347651 doi:http://dx.doi.org/10.1016/j.jmb.2017.03.023
|
