Protein Kinase Inhibitors: Insights into Drug Design from Structure

Noble, M.E.M.; Endicott, Jane; Johnson, L.N.

doi:10.1126/science.1095920

Cited by 1,161 publications

(893 citation statements)

References 63 publications

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“…lanes 8 and 11), the chromatin association of c-ABL-kd was minimal (first row, lanes 9 and 12), indicating that the efficient chromatin association of c-ABL requires intact tyrosine kinase activity. This was further confirmed by the results of experiment with imatinib, a specific inhibitor of c-ABL [21], that imatinib effectively inhibits c-ABL chromatin association (Supplementary Fig. 3).…”

Section: Resultssupporting

confidence: 71%

c-ABL tyrosine kinase stabilizes RAD51 chromatin association

Shimizu

Popova

Fleury

et al. 2009

Biochemical and Biophysical Research Communications

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In this paper, by using self-association defective RAD51 mutants, we show that the phosphorylation of RAD51 by c-ABL stabilizes RAD51 chromatin association. This activation is abolished by replacement of Tyr-315 with Phe, indicating that the phosphorylation of Tyr-315 is the origin of this activation. However, c-ABL cannot restore the defect of the self-association defective mutants in IR-induced nuclear focus formation, suggesting that c-ABL functions during the early phase of RAD51 chromatin assembly, before RAD51 nucleo-protein filament formation. Our findings thus suggest a new model for the regulation of early steps of homologous recombination repair.We are very happy if you kindly consider our manuscript for possible publication in AbstractThe assembly of RAD51 recombinase on DNA substrates at sites of breakage is essential for their repair by homologous recombination repair (HRR). The signaling pathway that triggers RAD51 assembly at damage sites to form subnuclear foci is unclear. Here, we provide evidence that c-ABL, a tyrosine kinase activated by DNA damage which phosphorylates RAD51 on Tyr-315, works at a previously unrecognized, proximal step to initiate RAD51 assembly. We first show that c-ABL associates with chromatin after DNA damage in a manner dependent on its kinase activity. Using RAD51 mutants that are unable to oligomerize to form a nucleoprotein filament, we separate RAD51 assembly on DNA to form foci into two steps: stable chromatin association followed by oligomerization. We show that phosphorylation on Tyr-315 by c-ABL is required for chromatin association of oligomerization-defective RAD51 mutants, but is insufficient to restore oligomerization. Our findings suggest a new model for the regulation of early steps of HRR.

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Section: Resultssupporting

confidence: 71%

c-ABL tyrosine kinase stabilizes RAD51 chromatin association

Shimizu

Popova

Fleury

et al. 2009

Biochemical and Biophysical Research Communications

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“…Immediately N-terminal to the hinge loop (aas 263-268) is the so-called gatekeeper residue, Y262 in IRAK4. The size and flexibility of the side chain of this residue generally determines whether an additional lipophilic subpocket, referred to as the "back pocket," is present adjacent to the ATP binding site (19). The most abundant gatekeeper residue in kinases is methionine, followed by leucine, threonine, and phenylalanine.…”

Section: Unique N-terminal Extension and Gatekeeper Residuementioning

confidence: 99%

Cutting Edge: IL-1 Receptor-Associated Kinase 4 Structures Reveal Novel Features and Multiple Conformations

Kuglstatter

Villaseñor

Shaw

et al. 2007

The Journal of Immunology

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IL-1R-associated kinase (IRAK)4 plays a central role in innate and adaptive immunity, and is a crucial component in IL-1/TLR signaling. We have determined the crystal structures of the apo and ligand-bound forms of human IRAK4 kinase domain. These structures reveal several features that provide opportunities for the design of selective IRAK4 inhibitors. The N-terminal lobe of the IRAK4 kinase domain is structurally distinctive due to a loop insertion after an extended N-terminal helix. The gatekeeper residue is a tyrosine, a unique feature of the IRAK family. The IRAK4 structures also provide insights into the regulation of its activity. In the apo structure, two conformations coexist, differing in the relative orientation of the two kinase lobes and the position of helix C. In the presence of an ATP analog only one conformation is observed, indicating that this is the active conformation.

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“…Small-molecule inhibitors for seven-transmembrane proteins and protein kinases are promising drugs in the postgenome era (60). KADD-cyclopamine, SANT1-4 and Cur61414 have been developed as small-molecule SMO inhibitors (57)(58)(59).…”

Section: Perspectivesmentioning

confidence: 99%