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[[Image:1svg.gif|left|200px]]


{{Structure
==Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 4==
|PDB= 1svg |SIZE=350|CAPTION= <scene name='initialview01'>1svg</scene>, resolution 2.02&Aring;
<StructureSection load='1svg' size='340' side='right'caption='[[1svg]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=I04:N-{(3R,4R)-4-[4-(2-FLUORO-6-HYDROXY-3-METHOXY-BENZOYL)-BENZOYLAMINO]-AZEPAN-3-YL}ISONICOTINAMIDE'>I04</scene>
<table><tr><td colspan='2'>[[1svg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SVG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SVG FirstGlance]. <br>
|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]  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.02&#8491;</td></tr>
|GENE= PRKACA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 Bos taurus])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I04:N-{(3R,4R)-4-[4-(2-FLUORO-6-HYDROXY-3-METHOXY-BENZOYL)-BENZOYLAMINO]-AZEPAN-3-YL}ISONICOTINAMIDE'>I04</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
}}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1svg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1svg OCA], [https://pdbe.org/1svg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1svg RCSB], [https://www.ebi.ac.uk/pdbsum/1svg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1svg ProSAT]</span></td></tr>
</table>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sv/1svg_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=1svg ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


'''Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 4'''
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<ref>PMID:14998327</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1svg" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
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.
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1SVG is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SVG OCA].
__TOC__
 
</StructureSection>
==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:[http://www.ncbi.nlm.nih.gov/pubmed/14998327 14998327]
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Berillon, L.]]
[[Category: Berillon L]]
[[Category: Breitenlechner, C B.]]
[[Category: Breitenlechner CB]]
[[Category: Engh, R A.]]
[[Category: Engh RA]]
[[Category: Friebe, W G.]]
[[Category: Friebe W-G]]
[[Category: Graul, K.]]
[[Category: Graul K]]
[[Category: Huber, R.]]
[[Category: Huber R]]
[[Category: Marzenell, K.]]
[[Category: Marzenell K]]
[[Category: Masjost, B.]]
[[Category: Masjost B]]
[[Category: Schumacher, R.]]
[[Category: Schumacher R]]
[[Category: Thomas, U.]]
[[Category: Thomas U]]
[[Category: Wegge, T.]]
[[Category: Wegge T]]
[[Category: I04]]
[[Category: balanol derivative]]
[[Category: kinase-inhibitor-complex]]
[[Category: serine/threonine-protein kinase]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:10:08 2008''

Latest revision as of 03:29, 21 November 2024

Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 4Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 4

Structural highlights

1svg is a 2 chain structure with sequence from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.02Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe WG, Thomas U, Schumacher R, Huber R, Engh RA, Masjost B. Structure-based optimization of novel azepane derivatives as PKB inhibitors. J Med Chem. 2004 Mar 11;47(6):1375-90. PMID:14998327 doi:http://dx.doi.org/10.1021/jm0310479

1svg, resolution 2.02Å

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