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PDBsum entry 1rek

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protein ligands links
Transferase PDB id
1rek
Jmol
Contents
Protein chain
338 a.a. *
Ligands
B8L
PTL
Waters ×99
* Residue conservation analysis
PDB id:
1rek
Name: Transferase
Title: Crystal structure of camp-dependent protein kinase complexed with balanol analog 8
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Synonym: pka c-alpha. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: prkaca, pkaca. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Resolution:
2.30Å     R-factor:   0.218     R-free:   0.295
Authors: P.Akamine,Madhusudan,L.L.Brunton,H.D.Ou,J.M.Canaves, N.H.Xuong,S.S.Taylor
Key ref:
P.Akamine et al. (2004). Balanol analogues probe specificity determinants and the conformational malleability of the cyclic 3',5'-adenosine monophosphate-dependent protein kinase catalytic subunit. Biochemistry, 43, 85-96. PubMed id: 14705934 DOI: 10.1021/bi035042p
Date:
06-Nov-03     Release date:   24-Feb-04    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P05132  (KAPCA_MOUSE) -  cAMP-dependent protein kinase catalytic subunit alpha
Seq:
Struc:
351 a.a.
338 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.11  - cAMP-dependent protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     sperm midpiece   16 terms 
  Biological process     regulation of proteasomal protein catabolic process   18 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi035042p Biochemistry 43:85-96 (2004)
PubMed id: 14705934  
 
 
Balanol analogues probe specificity determinants and the conformational malleability of the cyclic 3',5'-adenosine monophosphate-dependent protein kinase catalytic subunit.
P.Akamine, Madhusudan, L.L.Brunton, H.D.Ou, J.M.Canaves, N.H.Xuong, S.S.Taylor.
 
  ABSTRACT  
 
The protein kinase family is a prime target for therapeutic agents, since unregulated protein kinase activities are linked to myriad diseases. Balanol, a fungal metabolite consisting of four rings, potently inhibits Ser/Thr protein kinases and can be modified to yield potent inhibitors that are selective-characteristics of a desirable pharmaceutical compound. Here, we characterize three balanol analogues that inhibit cyclic 3',5'-adenosine monophosphate-dependent protein kinase (PKA) more specifically and potently than calcium- and phospholipid-dependent protein kinase (PKC). Correlation of thermostability and inhibition potency suggests that better inhibitors confer enhanced protection against thermal denaturation. Crystal structures of the PKA catalytic (C) subunit complexed to each analogue show the Gly-rich loop stabilized in an "intermediate" conformation, disengaged from important phosphoryl transfer residues. An analogue that perturbs the PKA C-terminal tail has slightly weaker inhibition potency. The malleability of the PKA C subunit is illustrated by active site residues that adopt alternate rotamers depending on the ligand bound. On the basis of sequence homology to PKA, a preliminary model of the PKC active site is described. The balanol analogues serve to test the model and to highlight differences in the active site local environment of PKA and PKC. The PKA C subunit appears to tolerate balanol analogues with D-ring modifications; PKC does not. We attribute this difference in preference to the variable B helix and C-terminal tail. By understanding the details of ligand binding, more specific and potent inhibitors may be designed that differentiate among closely related AGC protein kinase family members.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21254413 M.Yar, M.G.Unthank, E.M.McGarrigle, and V.K.Aggarwal (2011).
Remote chiral induction in vinyl sulfonium salt-mediated ring expansion of hemiaminals into epoxide-fused azepines.
  Chem Asian J, 6, 372-375.  
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
19152365 F.Fontaine, S.Cross, G.Plasencia, M.Pastor, and I.Zamora (2009).
SHOP: a method for structure-based fragment and scaffold hopping.
  ChemMedChem, 4, 427-439.  
17957770 Z.Huang, C.F.Wong, and R.A.Wheeler (2008).
Flexible protein-flexible ligand docking with disrupted velocity simulated annealing.
  Proteins, 71, 440-454.  
17933849 F.S.Domingues, J.Rahnenführer, and T.Lengauer (2007).
Conformational analysis of alternative protein structures.
  Bioinformatics, 23, 3131-3138.  
17036304 C.S.Page, and P.A.Bates (2006).
Can MM-PBSA calculations predict the specificities of protein kinase inhibitors?
  J Comput Chem, 27, 1990-2007.  
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
15706577 R.Paulini, K.Müller, and F.Diederich (2005).
Orthogonal multipolar interactions in structural chemistry and biology.
  Angew Chem Int Ed Engl, 44, 1788-1805.  
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.