2gni: Difference between revisions

Revision as of 09:29, 28 July 2008

This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.

File:2gni.png

Template:STRUCTURE 2gni

PKA fivefold mutant model of Rho-kinase with inhibitor Fasudil (HA1077)PKA fivefold mutant model of Rho-kinase with inhibitor Fasudil (HA1077)

Template:ABSTRACT PUBMED 16699172

About this StructureAbout this Structure

2GNI is a Protein complex structure of sequences from Bos taurus. Full crystallographic information is available from OCA.

ReferenceReference

Structural analysis of protein kinase A mutants with Rho-kinase inhibitor specificity., Bonn S, Herrero S, Breitenlechner CB, Erlbruch A, Lehmann W, Engh RA, Gassel M, Bossemeyer D, J Biol Chem. 2006 Aug 25;281(34):24818-30. Epub 2006 May 12. PMID:16699172

Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity., Breitenlechner C, Gassel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D, Structure. 2003 Dec;11(12):1595-607. PMID:14656443

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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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 {{STRUCTURE_2gni|  PDB=2gni  |  SCENE=  }}
-'''PKA fivefold mutant model of Rho-kinase with inhibitor Fasudil (HA1077)'''
+===PKA fivefold mutant model of Rho-kinase with inhibitor Fasudil (HA1077)===
-==Overview==
+<!--
-Controlling aberrant kinase-mediated cellular signaling is a major strategy in cancer therapy; successful protein kinase inhibitors such as Tarceva and Gleevec verify this approach. Specificity of inhibitors for the targeted kinase(s), however, is a crucial factor for therapeutic success. Based on homology modeling, we previously identified four amino acids in the active site of Rho-kinase that likely determine inhibitor specificities observed for Rho-kinase relative to protein kinase A (PKA) (in PKA numbering: T183A, L49I, V123M, and E127D), and a fifth (Q181K) that played a surprising role in PKA-PKB hybrid proteins. We have systematically mutated these residues in PKA to their counterparts in Rho-kinase, individually and in combination. Using four Rho-kinase-specific, one PKA-specific, and one pan-kinase-specific inhibitor, we measured the inhibitor-binding properties of the mutated proteins and identify the roles of individual residues as specificity determinants. Two combined mutant proteins, containing the combination of mutations T183A and L49I, closely mimic Rho-kinase. Kinetic results corroborate the hypothesis that side-chain identities form the major determinants of selectivity. An unexpected result of the analysis is the consistent contribution of the individual mutations by simple factors. Crystal structures of the surrogate kinase inhibitor complexes provide a detailed basis for an understanding of these selectivity determinant residues. The ability to obtain kinetic and structural data from these PKA mutants, combined with their Rho-kinase-like selectivity profiles, make them valuable for use as surrogate kinases for structure-based inhibitor design.
+The line below this paragraph, {{ABSTRACT_PUBMED_16699172}}, adds the Publication Abstract to the page
+(as it appears on PubMed at http://www.pubmed.gov), where 16699172 is the PubMed ID number.
+-->
+{{ABSTRACT_PUBMED_16699172}}
 ==About this Structure==
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 ==Reference==
 Structural analysis of protein kinase A mutants with Rho-kinase inhibitor specificity., Bonn S, Herrero S, Breitenlechner CB, Erlbruch A, Lehmann W, Engh RA, Gassel M, Bossemeyer D, J Biol Chem. 2006 Aug 25;281(34):24818-30. Epub 2006 May 12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16699172 16699172]
+Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity., Breitenlechner C, Gassel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D, Structure. 2003 Dec;11(12):1595-607. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14656443 14656443]
 [[Category: Bos taurus]]
 [[Category: Protein complex]]
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 [[Category: Rho-kinase]]
 [[Category: Surrogate]]
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