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PDBsum entry 1xh5
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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
1xh5

 

 

 

 

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Contents
Protein chains
337 a.a. *
20 a.a. *
Ligands
R68
BU3 ×3
Waters ×212
* Residue conservation analysis
PDB id:
1xh5
Name: Transferase/transferase inhibitor
Title: Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Synonym: protein kinase a, pka c-alpha. Engineered: yes. Camp-dependent protein kinase inhibitor, alpha form. Chain: b. Fragment: pki(residues 5-24). Synonym: protein kinase inhibitor peptide. 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. Synthetic construct. Organism_taxid: 32630.
Biol. unit: Dimer (from PQS)
Resolution:
2.05Å     R-factor:   0.185     R-free:   0.236
Authors: C.B.Breitenlechner,W.-G.Friebe,E.Brunet,G.Werner,K.Graul,U.Thomas,K.- P.Kuenkele,W.Schaefer,M.Gassel,D.Bossemeyer,R.Huber,R.A.Engh, B.Masjost
Key ref: C.B.Breitenlechner et al. (2005). Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants. J Med Chem, 48, 163-170. PubMed id: 15634010 DOI: 10.1021/jm049701n
Date:
17-Sep-04     Release date:   17-Sep-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 ?
P61925  (IPKA_HUMAN) -  cAMP-dependent protein kinase inhibitor alpha from Homo sapiens
Seq:
Struc: 		76 a.a.
20 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/jm049701n J Med Chem 48:163-170 (2005)
PubMed id: 15634010  
 
 
Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants.
C.B.Breitenlechner, W.G.Friebe, E.Brunet, G.Werner, K.Graul, U.Thomas, K.P.Künkele, W.Schäfer, M.Gassel, D.Bossemeyer, R.Huber, R.A.Engh, B.Masjost.
 
  ABSTRACT  
 
Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
18794885 C.Garcia-Echeverria, and W.R.Sellers (2008).
Drug discovery approaches targeting the PI3K/Akt pathway in cancer.
  Oncogene, 27, 5511-5526.  
18838385 M.H.Gao, T.Tang, T.Guo, A.Miyanohara, T.Yajima, K.Pestonjamasp, J.R.Feramisco, and H.K.Hammond (2008).
Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes.
  J Biol Chem, 283, 33527-33535.  
17613211 J.Riley, A.Spiotta, and N.Boulis (2007).
Experimental therapeutic approaches to peripheral nerve tumors.
  Neurosurg Focus, 22, E2.  
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.  
16288295 J.Q.Cheng, C.W.Lindsley, G.Z.Cheng, H.Yang, and S.V.Nicosia (2005).
The Akt/PKB pathway: molecular target for cancer drug discovery.
  Oncogene, 24, 7482-7492.  
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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