2gcd Citations

Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine.

Acta Biochim Biophys Sin (Shanghai) 38 385-92 (2006)

Abstract

Mitogen-activated protein kinase (MAPK) signal transduction pathways are ubiquitous in eukaryotic cells, which transfer signals from the cell surface to the nucleus, controlling multiple cellular programs. MAPKs are activated by MAPK kinases [MAP2Ks or MAP/extracellular signal-regulated kinase (ERK) kinases (MEK)], which in turn are activated by MAPK kinase kinases (MAP3Ks). TAO2 is a MAP3K level kinase that activates the MAP2Ks MEK3 and MEK6 to activate p38 MAPKs. Because p38 MAPKs are key regulators of expression of inflammatory cytokines, they appear to be involved in human diseases such as asthma and autoimmunity. As an upstream activator of p38s, TAO2 represents a potential drug target. Here we report the crystal structure of active TAO2 kinase domain in complex with staurosporine, a broad-range protein kinase inhibitor that inhibits TAO2 with an IC50 of 3 mM. The structure reveals that staurosporine occupies the position where the adenosine of ATP binds in TAO2, and the binding of the inhibitor mimics many features of ATP binding. Both polar and nonpolar interactions contribute to the enzyme-inhibitor recognition. Staurosporine induces conformational changes in TAO2 residues that surround the inhibitor molecule, but causes very limited global changes in the kinase. The structure provides atomic details for TAO2-staurosporine interactions, and explains the relatively low potency of staurosporine against TAO2. The structure presented here should aid in the design of inhibitors specific to TAO2 and related kinases.

Articles - 2gcd mentioned but not cited (4)

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  2. Research Support, Non-U.S. Gov't Considerations of Protein Subpockets in Fragment-Based Drug Design. Bartolowits M, Davisson VJ. Chem Biol Drug Des 87 5-20 (2016)
  3. Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach. Chao MW, Lin TE, HuangFu WC, Chang CD, Tu HJ, Chen LC, Yen SC, Sung TY, Huang WJ, Yang CR, Pan SL, Hsu KC. J Enzyme Inhib Med Chem 36 98-108 (2021)
  4. Novel 1,2,3-Triazole-Containing Quinoline-Benzimidazole Hybrids: Synthesis, Antiproliferative Activity, In Silico ADME Predictions, and Docking. Krstulović L, Mišković Špoljarić K, Rastija V, Filipović N, Bajić M, Glavaš-Obrovac L. Molecules 28 6950 (2023)


Reviews citing this publication (1)

  1. The Diverse Roles of TAO Kinases in Health and Diseases. Fang CY, Lai TC, Hsiao M, Chang YC. Int J Mol Sci 21 E7463 (2020)

Articles citing this publication (2)

  1. Alkylation of Staurosporine to Derive a Kinase Probe for Fluorescence Applications. Disney AJ, Kellam B, Dekker LV. ChemMedChem 11 972-979 (2016)
  2. Staurosporine Analogs Via C-H Borylation. Gayler KM, Kong K, Reisenauer K, Taube JH, Wood JL. ACS Med Chem Lett 11 2441-2445 (2020)