1rek

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[[Image:1rek.gif|left|200px]]
[[Image:1rek.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1rek |SIZE=350|CAPTION= <scene name='initialview01'>1rek</scene>, resolution 2.3&Aring;
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The line below this paragraph, containing "STRUCTURE_1rek", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=B8L:3-[(3-SEC-BUTYL-4-HYDROXYBENZOYL)AMINO]AZEPAN-4-YL+4-(2-HYDROXY-5-METHOXYBENZOYL)BENZOATE'>B8L</scene>, <scene name='pdbligand=PTL:PENTANAL'>PTL</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= PRKACA, PKACA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])
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|DOMAIN=
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{{STRUCTURE_1rek| PDB=1rek | SCENE= }}
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|RELATEDENTRY=[[1re8|1RE8]], [[1rej|1REJ]], [[1bx6|1BX6]], [[1atp|1ATP]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1rek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rek OCA], [http://www.ebi.ac.uk/pdbsum/1rek PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1rek RCSB]</span>
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'''Crystal structure of cAMP-dependent protein kinase complexed with balanol analog 8'''
'''Crystal structure of cAMP-dependent protein kinase complexed with balanol analog 8'''
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[[Category: Taylor, S S.]]
[[Category: Taylor, S S.]]
[[Category: Xuong, N H.]]
[[Category: Xuong, N H.]]
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[[Category: conformational malleability]]
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[[Category: Conformational malleability]]
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[[Category: ligand binding]]
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[[Category: Ligand binding]]
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[[Category: natural product inhibitor]]
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[[Category: Natural product inhibitor]]
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[[Category: protein kinase]]
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[[Category: Protein kinase]]
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[[Category: specifity determinant]]
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[[Category: Specifity determinant]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:23:59 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:27:02 2008''
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Revision as of 04:24, 3 May 2008

Image:1rek.gif

Template:STRUCTURE 1rek

Crystal structure of cAMP-dependent protein kinase complexed with balanol analog 8


Overview

The protein kinase family is a prime target for therapeutic agents, since unregulated protein kinase activities are linked to myriad diseases. Balanol, a fungal metabolite consisting of four rings, potently inhibits Ser/Thr protein kinases and can be modified to yield potent inhibitors that are selective-characteristics of a desirable pharmaceutical compound. Here, we characterize three balanol analogues that inhibit cyclic 3',5'-adenosine monophosphate-dependent protein kinase (PKA) more specifically and potently than calcium- and phospholipid-dependent protein kinase (PKC). Correlation of thermostability and inhibition potency suggests that better inhibitors confer enhanced protection against thermal denaturation. Crystal structures of the PKA catalytic (C) subunit complexed to each analogue show the Gly-rich loop stabilized in an "intermediate" conformation, disengaged from important phosphoryl transfer residues. An analogue that perturbs the PKA C-terminal tail has slightly weaker inhibition potency. The malleability of the PKA C subunit is illustrated by active site residues that adopt alternate rotamers depending on the ligand bound. On the basis of sequence homology to PKA, a preliminary model of the PKC active site is described. The balanol analogues serve to test the model and to highlight differences in the active site local environment of PKA and PKC. The PKA C subunit appears to tolerate balanol analogues with D-ring modifications; PKC does not. We attribute this difference in preference to the variable B helix and C-terminal tail. By understanding the details of ligand binding, more specific and potent inhibitors may be designed that differentiate among closely related AGC protein kinase family members.

About this Structure

1REK is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

Reference

Balanol analogues probe specificity determinants and the conformational malleability of the cyclic 3',5'-adenosine monophosphate-dependent protein kinase catalytic subunit., Akamine P, Madhusudan, Brunton LL, Ou HD, Canaves JM, Xuong NH, Taylor SS, Biochemistry. 2004 Jan 13;43(1):85-96. PMID:14705934 Page seeded by OCA on Sat May 3 07:23:59 2008

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