Tyrosine kinase

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{{STRUCTURE_3ac1| PDB=3ac1 | SIZE=400| SCENE= |right|CAPTION=Human lymphocyte-specific tyrosine kinase Lck kinase domain with phosphotyrosine complex with inhibitor, MPD, dimethyl sulfoxide and sulfate, [[3ac1]] }}
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<StructureSection load='' size='350' side='right' scene='48/483859/Cv/1' caption='Human Fyn tyrosine kinase kinase domain with phosphotyrosine in stick model complex with inhibitor staurosporine (PDB code [[2dq7]]).' pspeed='8'>
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__TOC__
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==Function==
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'''Tyrosine kinase''' (TK) transfers a phosphate group from ATP to tyrosine residues of proteins. Mutated TK can cause unregulated growth of the cell and their inhibitors can be effective cancer treatment. See [[Tyrosine Kinase Inhibitor Pharmacokinetics]]. For references see [[Treatments:TYKI References]].
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'''Tyrosine kinase''' (TK) transfers a phosphate group from ATP to tyrosine residues of proteins<ref>PMID:10966463</ref>. TKs are classified as [[Receptor tyrosine kinases|receptor-TK]] which are membrane-attached and cytoplasmic non-receptor TKs. Staurosporine inhibits TK and prevents ATP binding to it.<br />
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For '''Abelson tyrosine kinase''' see:<br />
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{{TOC limit|limit=2}}
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*[[Bcr-Abl and Imatinib (STI571 or Gleevec)]]<br />
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*[[Imatinib]] (Gleevec)<br />
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==3D structures of tyrosine kinase==
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*[[Dasatinib]] (Sprycel)<br />
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*[[Nilotinib]] (Tasigna)<br />
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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For '''Bruton's tyrosine kinase''' see:<br />
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*[[Ibrutinib]] (Imbruvica)<br />
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===Fyn tyrosine kinase===
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For '''Src tyrosine kinase'''<ref>PMID:15504335</ref> see:<br />
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*[[SRC]]<br />
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[[1shf]] – hTK Fyn SH3 domain – human<br />
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For '''Kit tyrosine kinase''' (or SCF or stem cell factor) see:<br />
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[[3h0f]], [[3h0h]], [[3h0i]] - hTK Fyn SH3 domain (mutant)
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*[[SCF-KIT]]<br />
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For '''Tyk tyrosine kinase''' see:<br />
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''Fyn complex''
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*[[Student Project 5 for UMass Chemistry 423 Spring 2015]]<br />
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*[[Ephrin receptor|Ephrin receptors]] belong to the receptor tyrosine kinases.
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[[1fyn]] - hTK Fyn SH3 domain + peptide<br />
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For '''Focal adhesion kinase''' see:<br />
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[[1efn]], [[1avz]] - hTK Fyn SH3 domain + HIV Nef protein<br />
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*[[Focal adhesion kinase]]
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[[1aot]], [[1aou]] - hTK Fyn SH2 domain + phosphopeptide - NMR<BR />
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*'''Csk tyrosine kinase''' (or C-terminal Src kinase) has a role in regulating apoptosis, survival, proliferation<ref>PMID:36578781</ref>.
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*'''Fgr tyrosine kinase''' has a role in regulating diet-induced obesity, insulin resistance and liver steatosis<ref>PMID:32943786</ref>.
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===Abelson tyrosine kinase===
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*'''Syk tyrosine kinase''' (or spleen tyrosine kinase) has a role in adaptive immun receptor signalling<ref>PMID:20467426</ref>.
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*'''Mer tyrosine kinase''' has a role in macrophage physiology like regulating cytokine secretion and clearance of apoptotic cells<ref>PMID:19386698</ref>.
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[[1ab2]], [[2ecd]] - hTK abl SH2 domain – NMR<BR />
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*'''Hck tyrosine kinase''' activates kinase-dependent and caspase-mediated apoptosis<ref>PMID:14551197</ref>.
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[[2abl]] - hTK abl SH3-SH2 domain<br />
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See also
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[[2kk1]] – hTK abl C terminal – NMR<BR />
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[[1abq]] - mTK abl SH2 domain - mouse
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*[[Proto-oncogene tyrosine-protein kinase]]<br />
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*[[Tyrosine Kinase Inhibitor Pharmacokinetics]]<br />
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''abl complex''
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*[[Treatments:TYKI References]]<br />
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*[[Oncogenes & Tumor Suppressor Genes]]
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[[1awo]] - hTK abl SH3 domain + phosphopeptide – NMR<BR />
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*[[Cancer]]
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[[1bbz]] - hTK abl SH3 domain + peptide<br />
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*[[Ephrin Type-A Receptor]]
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[[2g2i]] - hTK abl kinase domain + peptide<br />
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[[3gvu]] - hTK abl kinase domain + Gleevec<br />
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[[3hmi]] - hTK abl kinase domain + inhibitor<br />
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[[1abo]] - mTK abl SH2 domain + peptide<br />
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===Bruton’s tyrosine kinase===
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[[2z0p]] - hTK Btk PH domain<br />
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[[1btk]] – hTK Btk PH domain (mutant) <br />
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[[3p08]] - hTK Btk kinase domain<br />
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[[1aww]], [[1awx]], [[1qly]] - hTK Btk SH3 domain – NMR<BR />
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[[2ge9]] - hTK Btk SH2 domain – NMR<BR />
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''Btk complex''
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[[1b55]] - hTK Btk PH domain + inositol-tetrakisphosphate<br />
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[[1bwn]] - hTK Btk PH domain (mutant) + inositol-tetrakisphosphate<br />
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[[3gen]], [[3ocs]], [[3pix]], [[3piy]], [[3piz]], [[3pj1]], [[3pj2]], [[3pj3]] - hTK Btk kinase domain + inhibitor<br />
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[[3k54]], [[3t9t]] - hTK Btk kinase domain (mutant) + inhibitor<br />
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[[3oct]] - hTK Btk kinase domain (mutant) + dasatinib
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===p55-blk tyrosine kinase===
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[[1blj]], [[1blk]] - mTK p55-blk SH2 domain – NMR<BR />
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===Src tyrosine kinase===
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[[1yi6]] - hTK Src C terminal<br />
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[[1srl]], [[1srm]] - TK Src SH3 domain – chicken – NMR<BR />
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''Src complex''
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[[1spr]] - RsvTK Src SH2 domain + phosphate – Rous sarcoma virus<br />
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[[1kc2]] - RsvTK Src SH2 domain + peptide<br />
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===Lymphocyte-specific tyrosine kinase Lck===
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[[1kik]], [[1h92]] - hTK Lck SH3 domain – NMR<BR />
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[[2iim]] - hTK Lck SH3 domain<br />
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[[4d8k]], [[1x27]] - hTK Lck SH3-SH2 domain<br />
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[[3lck]] - hTK Lck kinase domain<br />
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''Lck complex''
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[[1lcj]], [[1lkk]], [[1lkl]] - hTK Lck SH2 domain (mutant) + phosphopeptide<br />
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[[1cwd]], [[1cwe]], [[1ijr]] - hTK Lck SH2 domain + phosphopeptide<br />
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[[1bhf]] - hTK Lck SH2 domain + peptide inhibitor<br />
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[[1fbz]] - hTK Lck SH2 domain + inhibitor<br />
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[[1bhh]] - hTK Lck SH2 domain + T-lymphocyte-specific TK<br />
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[[1lck]] - hTK Lck SH3-SH2 domain (mutant) + phosphopeptide<br />
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[[1x27]] - hTK Lck SH3-SH2 domain + peptide<br />
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[[1qpj]] - hTK Lck kinase domain + staurosporin<br />
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[[2of2]], [[2of4]], [[2ofu]], [[2ofv]], [[2og8]], [[3b2w]], [[3bym]], [[3bys]], [[3byu]], [[2zm1]], [[2zm4]], [[3byo]], [[2zyb]], [[3ac1]], [[3ac2]], [[3ac3]], [[3ac4]], [[3ac5]], [[3ac8]], [[3acj]], [[3ack]], [[3kmm]], [[3ad4]], [[3ad5]], [[3ad6]], [[1qpc]], [[1qpd]], [[1qpe]] - hTK Lck kinase domain + inhibitor<br />
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[[3mpm]] - hTK Lck kinase domain (mutant) + inhibitor<br />
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[[2pl0]] - hTK Lck kinase domain + imatinib<br />
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[[3kxz]] - hTK Lck kinase domain + probe molecule
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===Syk - spleen tyrosine kinase===
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[[1xba]] – Syk kinase domain
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''Syk complex''
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[[1xbb]] - Syk kinase domain + Gleevec<br />
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[[1xbc]] - Syk kinase domain + staurosporin<br />
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[[3emg]], [[3fqe]], [[3fqh]], [[3fqs]], [[3srv]], [[4dfl]], [[4dfn]], [[3vf8]], [[3vf9]], [[3tub]], [[3tuc]], [[3tud]], [[4f4p]], [[4fyn]], [[4fyo]], [[4fz6]] - Syk kinase domain + inhibitor<br />
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[[1csy]], [[1csz]] - Syk SH2 domain + phosphopeptide – NMR<BR />
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[[4fl1]], [[4fl2]] - Syk kinase domain + ANP<br />
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[[4fl3]] - Syk kinase domain (mutant) + ANP<br />
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[[1a81]] – Syk tandem SH2 domain + T-cell surface peptide <br />
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===Fms tyrosine kinase===
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[[2i0v]] - hTK Fms kinase domain
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For references see [[Treatments:TYKI References]].
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''Fms complex''
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==Relevance==
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[[2i0y]], [[2i1m]] - hTK Fms kinase domain + inhibitor<br />
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Bcr-Abl inhibitors are used against chronic myelogenous leukemia (CLM)<ref>PMID:19538165</ref>.
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[[3dpk]] - hTK Fms kinase domain (mutant) + inhibitor<br />
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[[1flt]] – hTK Fms Igg-like domain + VEGF<br />
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[[1qty]] - hTK Fms domain 2 + VEGF
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===Itk tyrosine kinase===
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==Disease==
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Mutated TK can cause unregulated growth of the cell and their inhibitors can be effective cancer treatment<ref>PMID:17311534</ref>.
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[[1lui]], [[1luk]], [[1lum]], [[1lun]] – mTK Itk SH2 domain – NMR<BR />
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== Structural highlights ==
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TK contains, starting from the N-terminal, SH4 – a membrane attachment domain; SH3 and SH2 domains which are a sequence-specific phosphotyrosine binding domains with roles in protein-protein interactions and the SH1 catalytic kinase domain. The <scene name='48/483859/Cv/6'>staurosporine inhibitor binds the kinase domain</scene> of Fyn TK which contains a <scene name='48/483859/Cv/7'>phosphotyrosine</scene>, in the <scene name='48/483859/Cv/8'>groove between the N- and C-lobes</scene><ref>PMID:16782058</ref>.
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===Zap tyrosine kinase===
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==Traditional Chinese medicine as dual guardians against hypertension and cancer? <ref>DOI 10.1080/07391102.2012.680030</ref> ==
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[[2ozo]] - hTK Zap (mutant) <br />
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<scene name='Journal:JBSD:14/Cv/2'>Src kinase</scene> functions as a signal protein and is implicated in various diseases. The carboxyl terminal of Src kinase is important in regulating conformation and activity of Src. Src protein is locked as an inward folding conformation through binding between the phosphorylated Tyr527 and the SH2 domain under normal inactive conditions. Src is activated when dephosphorylation of Tyr527 and phosphorylation of Tyr419 occurs.
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[[1m61]] - hTK Zap SH2 domain
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From N-terminal to C-terminal, Src is composed of a <scene name='Journal:JBSD:14/Cv/3'>smaller amino-terminal lobe</scene> (<span style="color:violet;background-color:black;font-weight:bold;">residues 270–340; colored in violet</span>) which binds adenosine triphosphate (ATP) and a <scene name='Journal:JBSD:14/Cv/5'>larger carboxyl-terminal lobe</scene> (<span style="color:lime;background-color:black;font-weight:bold;">residues 345–523; colored in green</span>) which binds with substrates. The ATP binding site is also partially located in the larger lobe. By regulating the alpha-helix structure, the large lobe can move toward or away from the small lobe, opening or closing the cleft between the two lobes. The Src catalytic site is located within the cleft. An open conformation allows the entrance of ATP into the cleft and exit of adenosine diphosphate (ADP) from the cleft. Drugs that can either interact with the residues (404–432) on the activation loop or inhibit the activation loop from moving away and opening the cleft as a result of Tyr419 phosphorylation can effectively inhibit Src activity.
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In this ''in vivo'' study, <scene name='Journal:JBSD:14/Cv/7'>Angeliferulate</scene> and <scene name='Journal:JBSD:14/Cv/8'>HMID</scene> have multiple stable interactions with the two Src cleft loops while simultaneously interacting with Asp407, hindering the activation loop from activation. Considering the aforementioned interactions with Src and high af&#64257;nity with EGFR, HER2, and HSP90, we suggest that Angeliferulate and HMID which both originate from the TCM ''Angelica sinensis'' may have potential as multi-targeting drug leads.
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''Zap complex''
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==3D structures of tyrosine kinase==
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[[Tyrosine kinase 3D structures]]
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[[2oq1]] - hTK Zap SH2 domain + peptide<br />
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[[1u59]] - hTK Zap catalytic domain + staurosporin
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===Mer tyrosine kinase===
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[[2dbj]] - hTK Mer FN2 domain – NMR<BR />
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[[2p0c]] - hTK Mer catalytic domain
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''Mer complex''
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[[3brb]] - hTK Mer catalytic domain + ADP<br />
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[[3bpr]] - hTK Mer catalytic domain + inhibitor<br />
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===Bone marrow tyrosine kinase===
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[[2ekx]] - hTK Bmx SH2 domain – NMR<BR />
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[[2ys2]] - hTK Bmx Btk motif – NMR<BR />
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''Bmx complex''
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[[3sxr]] - hTK Bmx kinase domain (mutant) + dasatinib<br />
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[[3sxs]] - hTK Bmx kinase domain (mutant) + inhibitor<br />
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===2β tyrosine kinase===
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[[3cc6]], [[3fzo]] - hTK Pyk2 kinase domain <br />
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[[3gm2]] - hTK Pyk2 FAT domain<br />
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[[3gm3]] - hTK Pyk2 FAT domain (mutant)
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''Pyk2 complex''
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[[3fzp]] - hTK Pyk2 kinase domain + ATPγS<br />
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[[3fzr]], [[3fzs]], [[3fzt]], [[3h3c]], [[3et7]] - hTK Pyk2 kinase domain + inhibitor<br />
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[[3gm1]] - hTK Pyk2 FAT domain + paxillin peptide<br />
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===CapAB tyrosine kinase===
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[[3bfv]] - SaTK CapA1/CapB2 – ''Staphylococcus aureus'' <br />
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[[2ved]] - SaTK CapA1/CapB2 + Mg + ADP
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===Fer tyrosine kinase===
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[[2kk6]] - hTK Fer SH2 domain – NMR<BR />
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===C-Src tyrosine kinase===
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[[C-Src tyrosine kinase]]
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==References==
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<references/>
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</StructureSection>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Human Fyn tyrosine kinase kinase domain with phosphotyrosine in stick model complex with inhibitor staurosporine (PDB code 2dq7).

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Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky, Joel L. Sussman

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