2I0E

Structure of catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor

Summary for 2I0E

• Entry DOI: 10.2210/pdb2i0e/pdb
• Descriptor: Protein Kinase C-beta II, 3-{1-[3-(DIMETHYLAMINO)PROPYL]-2-METHYL-1H-INDOL-3-YL}-4-(2-METHYL-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE (3 entities in total)
• Functional Keywords: protein kinase c beta ii, protein kinase c, serine/threonine protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): P05771
• Total number of polymer chains: 2
• Total formula weight: 82473.79

Authors

Grodsky, N.B.,Love, R.L. (deposition date: 2006-08-10, release date: 2006-11-14, Last modification date: 2024-11-20)

Primary citation

Grodsky, N.,Li, Y.,Bouzida, D.,Love, R.,Jensen, J.,Nodes, B.,Nonomiya, J.,Grant, S.
Structure of the Catalytic Domain of Human Protein Kinase C beta II Complexed with a Bisindolylmaleimide Inhibitor
Biochemistry, 45:13970-13981, 2006

PubMed Abstract: 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.

PubMed: 17115692
DOI: 10.1021/bi061128h

Experimental method

X-RAY DIFFRACTION (2.6 Å)