2i0e: Difference between revisions

Revision as of 18:47, 21 February 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 with 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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OCA

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-[[Image:2i0e.gif|left|200px]]<br />
+[[Image:2i0e.gif|left|200px]]<br /><applet load="2i0e" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2i0e" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2i0e, resolution 2.60&Aring;" />
 '''Structure of catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor'''<br />
 ==Overview==
-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.
+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 Structure==
-I0E 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 PDS as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2I0E OCA].
+I0E 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=PDS:'>PDS</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I0E OCA].
 ==Reference==
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 [[Category: Protein kinase C]]
 [[Category: Single protein]]
-[[Category: Grodsky, N.B.]]
+[[Category: Grodsky, N B.]]
-[[Category: Love, R.L.]]
+[[Category: Love, R L.]]
 [[Category: PDS]]
 [[Category: protein kinase c]]
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 [[Category: serine/threonine protein kinase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:39:15 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:47:44 2008''