2gfc

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(New page: 200px<br /><applet load="2gfc" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gfc, resolution 1.87&Aring;" /> '''cAMP-dependent prote...)
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[[Image:2gfc.gif|left|200px]]<br /><applet load="2gfc" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2gfc, resolution 1.87&Aring;" />
 
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'''cAMP-dependent protein kinase PKA catalytic subunit with PKI-5-24'''<br />
 
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==Overview==
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==cAMP-dependent protein kinase PKA catalytic subunit with PKI-5-24==
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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.
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<StructureSection load='2gfc' size='340' side='right'caption='[[2gfc]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2gfc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GFC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GFC FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.87&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OCT:N-OCTANE'>OCT</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2gfc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gfc OCA], [https://pdbe.org/2gfc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gfc RCSB], [https://www.ebi.ac.uk/pdbsum/2gfc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gfc ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/IPKA_RABIT IPKA_RABIT] Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gf/2gfc_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2gfc ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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2GFC is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with OCT as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2GFC OCA].
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*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=16699172 16699172]
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[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Oryctolagus cuniculus]]
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[[Category: Bonn, S.]]
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[[Category: Bonn S]]
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[[Category: Bossemeyer, D.]]
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[[Category: Bossemeyer D]]
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[[Category: Breitenlechner, C.B.]]
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[[Category: Breitenlechner CB]]
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[[Category: Engh, R.A.]]
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[[Category: Engh RA]]
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[[Category: Gassel, M.]]
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[[Category: Gassel M]]
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[[Category: Herrero, S.]]
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[[Category: Herrero S]]
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[[Category: OCT]]
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[[Category: binary complex]]
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[[Category: peptide inhibitor]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 11:10:07 2007''
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Current revision

cAMP-dependent protein kinase PKA catalytic subunit with PKI-5-24

PDB ID 2gfc

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