1svh
From Proteopedia
(New page: 200px<br /> <applet load="1svh" size="450" color="white" frame="true" align="right" spinBox="true" caption="1svh, resolution 2.30Å" /> '''Crystal Structure o...) |
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| - | [[Image:1svh.gif|left|200px]]<br /> | + | [[Image:1svh.gif|left|200px]]<br /><applet load="1svh" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1svh" size=" | + | |
caption="1svh, resolution 2.30Å" /> | caption="1svh, resolution 2.30Å" /> | ||
'''Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8'''<br /> | '''Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Novel azepane derivatives were prepared and evaluated for protein kinase B | + | 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 Structure== | ==About this Structure== | ||
| - | 1SVH 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 I08 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:// | + | 1SVH 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 <scene name='pdbligand=I08:'>I08</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1SVH OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Berillon, L.]] | [[Category: Berillon, L.]] | ||
| - | [[Category: Breitenlechner, C | + | [[Category: Breitenlechner, C B.]] |
| - | [[Category: Engh, R | + | [[Category: Engh, R A.]] |
| - | [[Category: Friebe, W | + | [[Category: Friebe, W G.]] |
[[Category: Graul, K.]] | [[Category: Graul, K.]] | ||
[[Category: Huber, R.]] | [[Category: Huber, R.]] | ||
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[[Category: serine/threonine-protein kinase]] | [[Category: serine/threonine-protein kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:05:36 2008'' |
Revision as of 13:05, 21 February 2008
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Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8
Overview
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 Structure
1SVH is a Protein complex structure of sequences from Bos taurus with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 15:05:36 2008
Categories: Bos taurus | Non-specific serine/threonine protein kinase | Protein complex | Berillon, L. | Breitenlechner, C B. | Engh, R A. | Friebe, W G. | Graul, K. | Huber, R. | Marzenell, K. | Masjost, B. | Schumacher, R. | Thomas, U. | Wegge, T. | I08 | Balanol derivative | Kinase-inhibitor-complex | Serine/threonine-protein kinase
