2gcd: Difference between revisions

Revision as of 18:30, 21 February 2008

TAO2 kinase domain-staurosporine structure

OverviewOverview

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.

About this StructureAbout this Structure

2GCD is a Single protein structure of sequence from Rattus norvegicus with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine., Zhou TJ, Sun LG, Gao Y, Goldsmith EJ, Acta Biochim Biophys Sin (Shanghai). 2006 Jun;38(6):385-92. PMID:16761096

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-[[Image:2gcd.jpg|left|200px]]<br /><applet load="2gcd" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="2gcd, resolution 2.550&Aring;" />
 '''TAO2 kinase domain-staurosporine structure'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-GCD is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with STU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2GCD OCA].
+GCD is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=STU:'>STU</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GCD OCA].
 ==Reference==
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 [[Category: Rattus norvegicus]]
 [[Category: Single protein]]
-[[Category: Cobb, M.H.]]
+[[Category: Cobb, M H.]]
 [[Category: Earnest, S.]]
 [[Category: Gao, Y.]]
-[[Category: Goldsmith, E.J.]]
+[[Category: Goldsmith, E J.]]
 [[Category: Sun, L.]]
 [[Category: Zhou, T.]]
@@ Line 27: / Line 27: @@
 [[Category: tao2]]
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