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2rkp

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==Overview==
==Overview==
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CK2alpha is the catalytic subunit of protein kinase CK2 and a member of the CMGC family of eukaryotic protein kinases like the cyclin-dependent kinases, the MAP kinases and glycogen-synthase kinase 3. We present here a 1.6 A resolution crystal structure of a fully active C-terminal deletion mutant of human CK2alpha liganded by two sulfate ions, and we compare this structure systematically with representative structures of related CMGC kinases. The two sulfate anions occupy binding pockets at the activation segment and provide the structural basis of the acidic consensus sequence S/T-D/E-X-D/E that governs substrate recognition by CK2. The anion binding sites are conserved among those CMGC kinases. In most cases they are neutralized by phosphorylation of a neighbouring threonine or tyrosine side-chain, which triggers conformational changes for regulatory purposes. CK2alpha, however, lacks both phosphorylation sites at the activation segment and structural plasticity. Here the anion binding sites are functionally changed from regulation to substrate recognition. These findings underline the exceptional role of CK2alpha as a constitutively active enzyme within a family of strictly controlled protein kinases.
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The Ser/Thr kinase CK2 (previously called casein kinase 2) is composed of two catalytic chains (CK2alpha) attached to a dimer of noncatalytic subunits (CK2beta). CK2 is involved in suppression of apoptosis, cell survival, and tumorigenesis. To investigate these activities and possibly affect them, selective CK2 inhibitors are required. An often-used CK2 inhibitor is 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). In a complex structure with human CK2alpha, DRB binds to the canonical ATP cleft, but additionally it occupies an allosteric site that can be alternatively filled by glycerol. Inhibition kinetic studies corroborate the dual binding mode of the inhibitor. Structural comparisons reveal a surprising conformational plasticity of human CK2alpha around both DRB binding sites. After local rearrangement, the allosteric site serves as a CK2beta interface. This opens the potential to construct molecules interfering with the CK2alpha/CK2beta interaction.
==About this Structure==
==About this Structure==
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2RKP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=RFZ:'>RFZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=2RKP OCA].
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2RKP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=RFZ:'>RFZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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] Known structural/functional Sites: <scene name='pdbsite=AC1:Cl+Binding+Site+For+Residue+A+336'>AC1</scene>, <scene name='pdbsite=AC2:Cl+Binding+Site+For+Residue+A+337'>AC2</scene>, <scene name='pdbsite=AC3:Cl+Binding+Site+For+Residue+A+338'>AC3</scene>, <scene name='pdbsite=AC4:Cl+Binding+Site+For+Residue+A+339'>AC4</scene>, <scene name='pdbsite=AC5:Cl+Binding+Site+For+Residue+A+340'>AC5</scene>, <scene name='pdbsite=AC6:Cl+Binding+Site+For+Residue+A+341'>AC6</scene>, <scene name='pdbsite=AC7:Cl+Binding+Site+For+Residue+A+342'>AC7</scene>, <scene name='pdbsite=AC8:Cl+Binding+Site+For+Residue+A+343'>AC8</scene>, <scene name='pdbsite=AC9:Cl+Binding+Site+For+Residue+A+344'>AC9</scene>, <scene name='pdbsite=BC1:Cl+Binding+Site+For+Residue+A+345'>BC1</scene>, <scene name='pdbsite=BC2:Cl+Binding+Site+For+Residue+A+346'>BC2</scene>, <scene name='pdbsite=BC3:Cl+Binding+Site+For+Residue+A+347'>BC3</scene>, <scene name='pdbsite=BC4:Cl+Binding+Site+For+Residue+A+348'>BC4</scene>, <scene name='pdbsite=BC5:Cl+Binding+Site+For+Residue+A+349'>BC5</scene>, <scene name='pdbsite=BC6:Cl+Binding+Site+For+Residue+A+350'>BC6</scene>, <scene name='pdbsite=BC7:Cl+Binding+Site+For+Residue+A+351'>BC7</scene>, <scene name='pdbsite=BC8:Rfz+Binding+Site+For+Residue+A+352'>BC8</scene> and <scene name='pdbsite=BC9:Rfz+Binding+Site+For+Residue+A+353'>BC9</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RKP OCA].
==Reference==
==Reference==
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Evolved to be active: sulfate ions define substrate recognition sites of CK2alpha and emphasise its exceptional role within the CMGC family of eukaryotic protein kinases., Niefind K, Yde CW, Ermakova I, Issinger OG, J Mol Biol. 2007 Jul 13;370(3):427-38. Epub 2007 May 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17524418 17524418]
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The CK2alpha/CK2beta Interface of Human Protein Kinase CK2 Harbors a Binding Pocket for Small Molecules., Raaf J, Brunstein E, Issinger OG, Niefind K, Chem Biol. 2008 Feb;15(2):111-7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18291315 18291315]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: wnt signaling pathway]]
[[Category: wnt signaling pathway]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:48:09 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Mar 5 13:25:45 2008''

Revision as of 11:25, 5 March 2008

Image:2rkp.jpg

2rkp, resolution 1.56Å

Drag the structure with the mouse to rotate

Crystal structure of the catalytic subunit of human protein kinase CK2 with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole

Overview

The Ser/Thr kinase CK2 (previously called casein kinase 2) is composed of two catalytic chains (CK2alpha) attached to a dimer of noncatalytic subunits (CK2beta). CK2 is involved in suppression of apoptosis, cell survival, and tumorigenesis. To investigate these activities and possibly affect them, selective CK2 inhibitors are required. An often-used CK2 inhibitor is 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). In a complex structure with human CK2alpha, DRB binds to the canonical ATP cleft, but additionally it occupies an allosteric site that can be alternatively filled by glycerol. Inhibition kinetic studies corroborate the dual binding mode of the inhibitor. Structural comparisons reveal a surprising conformational plasticity of human CK2alpha around both DRB binding sites. After local rearrangement, the allosteric site serves as a CK2beta interface. This opens the potential to construct molecules interfering with the CK2alpha/CK2beta interaction.

About this Structure

2RKP is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Known structural/functional Sites: , , , , , , , , , , , , , , , , and . Full crystallographic information is available from OCA.

Reference

The CK2alpha/CK2beta Interface of Human Protein Kinase CK2 Harbors a Binding Pocket for Small Molecules., Raaf J, Brunstein E, Issinger OG, Niefind K, Chem Biol. 2008 Feb;15(2):111-7. PMID:18291315

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