5xp5
C-Src in complex with ATP-Chf
Structural highlights
FunctionSRC_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] Publication Abstract from PubMedATP analogues containing a CXY group in place of the alpha,beta-bridging oxygen atom are powerful chemical probes for studying ATP-dependent enzymes. A limitation of such probes has been that conventional synthetic methods generate a mixture of diastereomers when the bridging carbon substitution is nonequivalent (X not equal Y). We report here a novel method based on derivatization of a bisphosphonate precursor with a d-phenylglycine chiral auxiliary that enables preparation of the individual diastereomers of alpha,beta-CHF-ATP and alpha,beta-CHCl-ATP, which differ only in the configuration at the CHX carbon. When tested on a dozen divergent protein kinases, these individual diastereomers exhibit remarkable diastereospecificity (up to over 1000-fold) in utilization by the enzymes. This high selectivity can be exploited in an enzymatic approach to obtain the otherwise inaccessible diastereomers of alpha,beta-CHBr-ATP. The crystal structure of a tyrosine kinase Src bound to alpha,beta-CHX-ADP establishes the absolute configuration of the CHX carbon and helps clarify the origin of the remarkable diastereospecificity observed. We further synthesized the individual diastereomers of alpha,beta-CHF-gamma-thiol-ATP and demonstrated their utility in labeling a wide spectrum of kinase substrates. The novel ATP substrate analogues afforded by these two complementary strategies should have broad application in the study of the structure and function of ATP-dependent enzymes. Remarkably Stereospecific Utilization of ATP alpha,beta-Halomethylene Analogues by Protein Kinases.,Ni F, Kung A, Duan Y, Shah V, Amador CD, Guo M, Fan X, Chen L, Chen Y, McKenna CE, Zhang C J Am Chem Soc. 2017 Jun 14;139(23):7701-7704. doi: 10.1021/jacs.7b03266. Epub, 2017 Jun 2. PMID:28535041[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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