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3juh

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3juh, resolution 1.66Å ()
Ligands: , ,
Gene: csnk2a1 (Homo sapiens)
Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Related: 3h30, 3fwq, 1jwh, 2pvr, 1lp4
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Contents

Crystal structure of a mutant of human protein kinase CK2alpha with altered cosubstrate specificity

Publication Abstract from PubMed

Protein kinase CK2 (casein kinase 2) is a highly conserved and ubiquitously found eukaryotic serine/threonine kinase that plays a role in various cellular key processes like proliferation, apoptosis and circadian rhythm. One of its prominent biochemical properties is its ability to use GTP as well as ATP as a cosubstrate (dual-cosubstrate specificity). This feature is exceptional among eukaryotic protein kinases, and its biological significance is unknown. We describe here a mutant of the catalytic subunit of protein kinase CK2 (CK2alpha) from Homo sapiens (hsCK2alpha) with a clear and CK2-atypical preference for ATP compared to GTP. This mutant was designed on the basis of several structures of CK2alpha from Zea mays (zmCK2alpha) in complex with various ATP-competitive ligands. A structural overlay revealed the existence of a "purine base binding plane" harbouring the planar moiety of the respective ligand like the purine base of ATP and GTP. This purine base binding plane is sandwiched between the side-chains of Ile66 (Val66 in hsCK2alpha) and Met163, and it adopts a significantly different orientation than in prominent homologues like cAMP-dependent protein kinase (CAPK). By exchanging these two flanking amino acids (Val66Ala, Met163Leu) in hsCK2alpha(1-335), a C-terminally truncated variant of hsCK2alpha, the cosubstrate specificity shifted in the expected direction so that the mutant strongly favours ATP. A structure determination of the mutant in complex with an ATP-analogue confirmed the predicted change of the purine base binding plane orientation. An unexpected but in retrospect plausible consequence of the mutagenesis was, that the helix alpha D region, which is in the direct neighbourhood of the ATP-binding site, has adopted a conformation that is more similar to CAPK and less favourable for binding of GTP. These findings demonstrate that CK2alpha possesses sophisticated structural adaptations in favour of dual-cosubstrate specificity, suggesting that this property could be of biological significance.

Inclining the purine base binding plane in protein kinase CK2 by exchanging the flanking side-chains generates a preference for ATP as a cosubstrate., Yde CW, Ermakova I, Issinger OG, Niefind K, J Mol Biol. 2005 Mar 25;347(2):399-414. Epub 2005 Jan 18. PMID:15740749

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

3juh is a 2 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entries and 1ymi. Full crystallographic information is available from OCA.

See Also

Reference

  • Yde CW, Ermakova I, Issinger OG, Niefind K. Inclining the purine base binding plane in protein kinase CK2 by exchanging the flanking side-chains generates a preference for ATP as a cosubstrate. J Mol Biol. 2005 Mar 25;347(2):399-414. Epub 2005 Jan 18. PMID:15740749 doi:http://dx.doi.org/10.1016/j.jmb.2005.01.003
  • Raaf J, Brunstein E, Issinger OG, Niefind K. The CK2 alpha/CK2 beta interface of human protein kinase CK2 harbors a binding pocket for small molecules. Chem Biol. 2008 Feb;15(2):111-7. PMID:18291315 doi:http://dx.doi.org/10.1016/j.chembiol.2007.12.012
  • Niefind K, Issinger OG. Conformational plasticity of the catalytic subunit of protein kinase CK2 and its consequences for regulation and drug design. Biochim Biophys Acta. 2010 Mar;1804(3):484-92. Epub 2009 Sep 28. PMID:19796713 doi:10.1016/j.bbapap.2009.09.022
  • Niefind K, Raaf J, Issinger OG. Protein kinase CK2 in health and disease: Protein kinase CK2: from structures to insights. Cell Mol Life Sci. 2009 Jun;66(11-12):1800-16. PMID:19387553 doi:10.1007/s00018-009-9149-8

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