TAILIEUCHUNG - Báo cáo khoa học: Structural recognition of an optimized substrate for the ephrin family of receptor tyrosine kinases

Ephrin receptor tyrosine kinase A3 (EphA3, EC ) is a member of a unique branch of the kinome in which downstream signaling occurs in both ligand- and receptor-expressing cells. Consequently, the ephrins and ephrin receptor tyrosine kinases often mediate processes involving cell–cell con-tact, including cellular adhesion or repulsion, developmental remodeling and neuronal mapping. | Structural recognition of an optimized substrate for the ephrin family of receptor tyrosine kinases Tat S I Dsi ic1 2 lohn R AZollzo 1 AKHollo Alloli-I Iocco 1 A Parkor3 Riiniomin p Tiirk3 laid . dvio oil . aei ea a doodi I I luoLci . ai Ixei el Ijai I III I . ui and Sirano Dhe-Paganon1 2 1 StructuralGenomics Consortium University of Toronto Canada 2 Department of Physiology University of Toronto Canada 3 Department of Pharmacology Yale University Schoolof Medicine New Haven CT USA Keywords ephrin kinase peptide array receptor tyrosine kinase substrate recognition X-ray crystallography Correspondence S. Dhe-Paganon Structural Genomics Consortium University of Toronto 101 College Street Toronto Ontario M5G 1L7 Canada Fax 1 416 946 0880 Tel 1 416 946 3876 E-mail Received 4 May 2009 accepted 10 June 2009 doi Ephrin receptor tyrosine kinase A3 EphA3 EC is a member of a unique branch of the kinome in which downstream signaling occurs in both ligand- and receptor-expressing cells. Consequently the ephrins and ephrin receptor tyrosine kinases often mediate processes involving cell-cell contact including cellular adhesion or repulsion developmental remodeling and neuronal mapping. The receptor is also frequently overexpressed in invasive cancers including breast small-cell lung and gastrointestinal cancers. However little is known about direct substrates of EphA3 kinase and no chemical probes are available. Using a library approach we found a short peptide sequence that is a good substrate for EphA3 and is suitable for co-crystallization studies. Complex structures show multiple contacts between kinase and substrates in particular two residues undergo conformational changes and by mutation are found to be important for substrate binding and turnover. In addition a difference in catalytic efficiency between EPH kinase family members is observed. These results provide insight into the mechanism of .

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