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Kinase inhibitors

Pocket remedy

Nature Reviews Drug Discovery volume 1, page 253 (2002)Cite this article

p38 is a Ser/Thr kinase that has a crucial role in regulating the production of proinflammatory cytokines, and elevated levels of these cytokines are associated with several autoimmune diseases, such as rheumatoid arthritis, diabetes and inflammatory bowel disease. The researchers carried out a high-throughput screen for kinase inhibitors, and identified a diaryl urea that they called compound 1.

To define the binding mode of this new compound, Regan and colleagues determined the crystal structure of the human-p38–compound-1 complex. When an inhibitor binds to all known protein Ser/Thr kinases, the highly conserved Asp-Phe-Gly (DFG) motif within the active site, which is required for binding, forms a so-called 'DFG-in' conformation, in which the Phe residue is buried in a hydrophobic pocket in the groove between the two lobes of the kinase.

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References

ORIGINAL RESEARCH PAPER

  1. Pargellis, C. et al. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol 9, 268–272 (2002)

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FURTHER READING

  1. Lee, J. C. et al. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 47, 185–201 (2000)

    Article  CAS  Google Scholar 

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  1. Nature Reviews Molecular Cell Biology,

    Simon Frantz

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  1. Simon Frantz
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Frantz, S. Pocket remedy. Nat Rev Drug Discov 1, 253 (2002). https://doi.org/10.1038/nrd785

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  • DOI: https://doi.org/10.1038/nrd785

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