Kinases chemical genetics

Elphick LM, Lee SE, Gouvemeur V et al (2007) Using chemical genetics and ATP analogs to dissect protein kinase function. ACS Chem Biol 2 299-314... 

Structure-based design has been employed in some powerful examples of chemical genetics by teams led by Kevan Shokat and by John Koh. Shokat s team has studied the function of kinases by engineering designed modifications into both the kinase and kinase inhibitor ligand to create highly selective chemical tools that can then be used to probe the function of individual kinases in complex kinase cascades (for an explanation of the basic concept see Figure 3.6) [20],... 

Kenski DM, Zhang C, von Zastrow M, Shokat KM. Chemical genetic engineering of G protein-coupled receptor kinase 2. J. Biol. Chem. 2005 280 35051-35061. 

Burkard ME, Randall CL, Larochelle S, Zhang C, Shokat KM, Fisher RP, Jallepalli PV. Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells. Proc. Natl. Acad. Sci. U.S.A. 2007 104 4383-4388. 

D.J. Templeton, K.M. Shokat, A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases, Nat. Methods 2005, 2(6), 435-41. 

Figure 1.24 Orthogonal chemical genetics development of analog-sensitive kinase alleles (ASKAs).

Key words Chemical genetics. Chemical genomics. Chemical proteomics. Connectivity map, Epigenomics, AflSnity selection. Kinases... 

Unlike rapamycin, the majority of kinase inhibitors are ATP competitive, thus making die dissection of dieir effects more difficult because of off-target effects. The first rqiorted Akt inhibitor, A-443654, is a case in point. We thus turned to a chemical genetic approach to develop highly selective Akt inhibitors. Mutation of the... 

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