2GCD

TAO2 kinase domain-staurosporine structure

2GCD の概要

• エントリーDOI: 10.2210/pdb2gcd/pdb
• 分子名称: Serine/threonine-protein kinase TAO2, STAUROSPORINE (3 entities in total)
• 機能のキーワード: tao2, map3k, inhibitor, staurosporine, transferase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cytoplasmic vesicle membrane ; Multi-pass membrane protein . Isoform 2: Cell projection, dendrite: Q9JLS3
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71806.15

構造登録者

Zhou, T.,Sun, L.,Gao, Y.,Earnest, S.,Cobb, M.H.,Goldsmith, E.J. (登録日: 2006-03-14, 公開日: 2006-09-05, 最終更新日: 2024-11-13)

主引用文献

Zhou, T.J.,Sun, L.G.,Gao, Y.,Goldsmith, E.J.
Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine.
Acta Biochim.Biophys.Sinica, 38:385-392, 2006

PubMed 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.

PubMed: 16761096

実験手法

X-RAY DIFFRACTION (2.55 Å)