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PDBsum entry 1svh
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protein ligands Protein-protein interface(s) links
Transferase PDB id
1svh

 

 

 

 

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Contents
Protein chains
337 a.a. *
19 a.a. *
Ligands
I08
Waters ×156
* Residue conservation analysis
PDB id:
1svh
Name: Transferase
Title: Crystal structure of protein kinase a in complex with azepane derivative 8
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Synonym: pka c-alpha, protein kinase a. Engineered: yes. Camp-dependent protein kinase inhibitor, alpha form. Chain: b. Fragment: residues 5-24. Synonym: pki-alpha, camp-dependent protein kinase inhibitor, muscle/brain isoform.
Source: Bos taurus. Cattle. Organism_taxid: 9913. Gene: prkaca. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the peptide occurs naturally in humans.
Biol. unit: Dimer (from PQS)
Resolution:
2.30Å     R-factor:   0.214     R-free:   0.259
Authors: C.B.Breitenlechner,T.Wegge,L.Berillon,K.Graul,K.Marzenell,W.G.Friebe, U.Thomas,R.Schumacher,R.Huber,R.A.Engh,B.Masjost
Key ref: C.B.Breitenlechner et al. (2004). Structure-based optimization of novel azepane derivatives as PKB inhibitors. J Med Chem, 47, 1375-1390. PubMed id: 14998327 DOI: 10.1021/jm0310479
Date:
29-Mar-04     Release date:   29-Mar-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha from Bos taurus
Seq:
Struc: 		351 a.a.
337 a.a.*
Protein chain
Pfam   ArchSchema ?
P63249  (IPKA_RAT) -  cAMP-dependent protein kinase inhibitor alpha from Rattus norvegicus
Seq:
Struc: 		76 a.a.
19 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.2.7.11.11  - cAMP-dependent protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/jm0310479 J Med Chem 47:1375-1390 (2004)
PubMed id: 14998327  
 
 
Structure-based optimization of novel azepane derivatives as PKB inhibitors.
C.B.Breitenlechner, T.Wegge, L.Berillon, K.Graul, K.Marzenell, W.G.Friebe, U.Thomas, R.Schumacher, R.Huber, R.A.Engh, B.Masjost.
 
  ABSTRACT  
 
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]-azepan-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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20128603 J.J.Tesmer, V.M.Tesmer, D.T.Lodowski, H.Steinhagen, and J.Huber (2010).
Structure of human G protein-coupled receptor kinase 2 in complex with the kinase inhibitor balanol.
  J Med Chem, 53, 1867-1870.
PDB codes: 3cik 3krw 3krx
20151677 T.McHardy, J.J.Caldwell, K.M.Cheung, L.J.Hunter, K.Taylor, M.Rowlands, R.Ruddle, A.Henley, A.de Haven Brandon, M.Valenti, T.G.Davies, L.Fazal, L.Seavers, F.I.Raynaud, S.A.Eccles, G.W.Aherne, M.D.Garrett, and I.Collins (2010).
Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).
  J Med Chem, 53, 2239-2249.
PDB codes: 2x37 2x39 2xh5
19734051 L.Du-Cuny, Z.Song, S.Moses, G.Powis, E.A.Mash, E.J.Meuillet, and S.Zhang (2009).
Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain.
  Bioorg Med Chem, 17, 6983-6992.  
18711718 Z.Huang, and C.F.Wong (2009).
Conformational selection of protein kinase A revealed by flexible-ligand flexible-protein docking.
  J Comput Chem, 30, 631-644.  
18794885 C.Garcia-Echeverria, and W.R.Sellers (2008).
Drug discovery approaches targeting the PI3K/Akt pathway in cancer.
  Oncogene, 27, 5511-5526.  
17471291 E.C.Nelson, C.P.Evans, P.C.Mack, R.W.Devere-White, and P.N.Lara (2007).
Inhibition of Akt pathways in the treatment of prostate cancer.
  Prostate Cancer Prostatic Dis, 10, 331-339.  
17555396 J.Y.Park, P.Y.Lin, and R.H.Weiss (2007).
Targeting the PI3K-Akt pathway in kidney cancer.
  Expert Rev Anticancer Ther, 7, 863-870.  
16249095 I.Collins, J.Caldwell, T.Fonseca, A.Donald, V.Bavetsias, L.J.Hunter, M.D.Garrett, M.G.Rowlands, G.W.Aherne, T.G.Davies, V.Berdini, S.J.Woodhead, D.Davis, L.C.Seavers, P.G.Wyatt, P.Workman, and E.McDonald (2006).
Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.
  Bioorg Med Chem, 14, 1255-1273.
PDB codes: 2c1a 2c1b
16699172 S.Bonn, S.Herrero, C.B.Breitenlechner, A.Erlbruch, W.Lehmann, R.A.Engh, M.Gassel, and D.Bossemeyer (2006).
Structural analysis of protein kinase A mutants with Rho-kinase inhibitor specificity.
  J Biol Chem, 281, 24818-24830.
PDB codes: 2gfc 2gnf 2gng 2gnh 2gni 2gnj 2gnl
16288296 C.C.Kumar, and V.Madison (2005).
AKT crystal structure and AKT-specific inhibitors.
  Oncogene, 24, 7493-7501.  
16009706 K.N.Thimmaiah, J.B.Easton, G.S.Germain, C.L.Morton, S.Kamath, J.K.Buolamwini, and P.J.Houghton (2005).
Identification of N10-substituted phenoxazines as potent and specific inhibitors of Akt signaling.
  J Biol Chem, 280, 31924-31935.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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