2i0e
Structure of catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor
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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 with PDS as ligand. Active as Protein kinase C, with EC number 2.7.11.13 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
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