1veb: Difference between revisions
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|PDB= 1veb |SIZE=350|CAPTION= <scene name='initialview01'>1veb</scene>, resolution 2.89Å | |PDB= 1veb |SIZE=350|CAPTION= <scene name='initialview01'>1veb</scene>, resolution 2.89Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=I05:(3R,4R)-N-{4-[4-(2-FLUORO-6-HYDROXY-3-METHOXY-BENZOYL)-BENZYLOXY]-AZEPAN-3-YL}-ISONICOTINAMIDE'>I05</scene> | |LIGAND= <scene name='pdbligand=I05:(3R,4R)-N-{4-[4-(2-FLUORO-6-HYDROXY-3-METHOXY-BENZOYL)-BENZYLOXY]-AZEPAN-3-YL}-ISONICOTINAMIDE'>I05</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene> | ||
|ACTIVITY= [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] | |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> | ||
|GENE= PRKACA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 Bos taurus]) | |GENE= PRKACA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 Bos taurus]) | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1sve|1SVE]], [[1svg|1SVG]], [[1svh|1SVH]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1veb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1veb OCA], [http://www.ebi.ac.uk/pdbsum/1veb PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1veb RCSB]</span> | |||
}} | }} | ||
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[[Category: Thomas, U.]] | [[Category: Thomas, U.]] | ||
[[Category: Wegge, T.]] | [[Category: Wegge, T.]] | ||
[[Category: balanol derivative]] | [[Category: balanol derivative]] | ||
[[Category: kinase-inhibitor-complex]] | [[Category: kinase-inhibitor-complex]] | ||
[[Category: serine/threonine-protein kinase]] | [[Category: serine/threonine-protein kinase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:23:10 2008'' | ||
Revision as of 00:23, 31 March 2008
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| , resolution 2.89Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | PRKACA (Bos taurus) | ||||||
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 | ||||||
| Related: | 1SVE, 1SVG, 1SVH
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 5
OverviewOverview
Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)amino]-azepan-4-yl ester (1) (IC(50) (PKB-alpha) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepa n-3-yl]-isonicotinamide (4), (3R,4R)-N-[4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3 -yl]-isonicotinamide (5), N-[(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl ]-azepan-3-yl)-isonicotinamide (6), N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan -3-yl]-isonicotinamide (7), and N-[(3R,4S)-4-(4-[trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl] -vinyl]-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1) Compound 4 was found to be plasma stable and highly active (IC(50) (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.
About this StructureAbout this Structure
1VEB is a Protein complex structure of sequences from Bos taurus. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based optimization of novel azepane derivatives as PKB inhibitors., Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe WG, Thomas U, Schumacher R, Huber R, Engh RA, Masjost B, J Med Chem. 2004 Mar 11;47(6):1375-90. PMID:14998327
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