3geq

Structural basis for the chemical rescue of Src kinase activityStructural basis for the chemical rescue of Src kinase activity

Structural highlights 3geq is a 2 chain structure with sequence from Gallus gallus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Gene: SRC (Gallus gallus) Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, RCSB, PDBsum 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 Protein tyrosine kinases are critical cell signaling enzymes. These enzymes have a highly conserved Arg residue in their catalytic loop which is present two residues or four residues downstream from an absolutely conserved Asp catalytic base. Prior studies on protein tyrosine kinases Csk and Src revealed the potential for chemical rescue of catalytically deficient mutant kinases (Arg to Ala mutations) by small diamino compounds, particularly imidazole; however, the potency and efficiency of rescue was greater for Src. This current study further examines the structural and kinetic basis of rescue for mutant Src as compared to mutant Abl tyrosine kinase. An X-ray crystal structure of R388A Src revealed the surprising finding that a histidine residue of the N-terminus of a symmetry-related kinase inserts into the active site of the adjacent Src and mimics the hydrogen-bonding pattern seen in wild-type protein tyrosine kinases. Abl R367A shows potent and efficient rescue more comparable to Src, even though its catalytic loop is more like that of Csk. Various enzyme redesigns of the active sites indicate that the degree and specificity of rescue are somewhat flexible, but the overall properties of the enzymes and rescue agents play an overarching role. The newly discovered rescue agent 2-aminoimidazole is about as efficient as imidazole in rescuing R/A Src and Abl. Rate vs pH studies with these imidazole analogues suggest that the protonated imidazolium is the preferred form for chemical rescue, consistent with structural models. The efficient rescue seen with mutant Abl points to the potential of this approach to be used effectively to analyze Abl phosphorylation pathways in cells. Comparative analysis of mutant tyrosine kinase chemical rescue.,Muratore KE, Seeliger MA, Wang Z, Fomina D, Neiswinger J, Havranek JJ, Baker D, Kuriyan J, Cole PA Biochemistry. 2009 Apr 21;48(15):3378-86. PMID:19260709 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine kinase

spinqualitylabelsall models 3geq, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image