2i0e: Difference between revisions
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'''Structure of catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor''' | '''Structure of catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor''' | ||
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[[Category: Grodsky, N B.]] | [[Category: Grodsky, N B.]] | ||
[[Category: Love, R L.]] | [[Category: Love, R L.]] | ||
[[Category: | [[Category: Protein kinase c]] | ||
[[Category: | [[Category: Protein kinase c beta ii]] | ||
[[Category: | [[Category: Serine/threonine protein kinase]] | ||
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Revision as of 06:55, 4 May 2008
Structure of catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor
OverviewOverview
The conventional protein kinase C isoform, PKCII, is a signaling kinase activated during the hyperglycemic state and has been associated with the development of microvascular abnormalities associated with diabetes. PKCII, therefore, has been identified as a therapeutic target where inhibitors of its kinase activity are being pursued for treatment of microvascular-related diabetic complications. In this report, we describe the crystal structure of the catalytic domain of PKCbetaII complexed with an inhibitor at 2.6 A resolution. The kinase domain of PKCbetaII was cleaved and purified from full-length PKCbetaII expressed in baculovirus-infected insect cells. The overall kinase domain structure follows the classical bilobal fold and is in its fully activated conformation with three well-defined phosphorylated residues: Thr-500, Thr-641, and Ser-660. Different from the crystal structures of nonconventional PKC isoforms, the C-terminus of the PKCbetaII catalytic domain is almost fully ordered and features a novel alpha helix in the turn motif. An ATP-competitive inhibitor, 2-methyl-1H-indol-3-yl-BIM-1, was crystallized with the PKCbetaII catalytic domain as a dimer of two enzyme-inhibitor complexes. The bound inhibitor adopts a nonplanar conformation in the ATP-binding site, with the kinase domain taking on an intermediate, open conformation. This PKCbetaII-inhibitor complex represents the first structural description of any conventional PKC kinase domain. Given the pathogenic role of PKCbetaII in the development of diabetic complications, this structure can serve as a template for the rational design of inhibitors as potential therapeutic agents.
About this StructureAbout this Structure
2I0E is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structure of the catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor., Grodsky N, Li Y, Bouzida D, Love R, Jensen J, Nodes B, Nonomiya J, Grant S, Biochemistry. 2006 Nov 28;45(47):13970-81. PMID:17115692 Page seeded by OCA on Sun May 4 06:55:41 2008