spacer
spacer

PDBsum entry 1p5e

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Cell cycle PDB id
1p5e
Jmol
Contents
Protein chains
297 a.a. *
258 a.a. *
Ligands
TBS ×2
Waters ×242
* Residue conservation analysis
PDB id:
1p5e
Name: Cell cycle
Title: The strucure of phospho-cdk2/cyclin a in complex with the inhibitor 4,5,6,7-tetrabromobenzotriazole (tbs)
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase. Engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 175-432. Synonym: cyclin a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ccna2 or ccna or ccn1.
Biol. unit: Dimer (from PQS)
Resolution:
2.22Å     R-factor:   0.219     R-free:   0.257
Authors: E.De Moliner,N.R.Brown,L.N.Johnson
Key ref:
E.De Moliner et al. (2003). Alternative binding modes of an inhibitor to two different kinases. Eur J Biochem, 270, 3174-3181. PubMed id: 12869192 DOI: 10.1046/j.1432-1033.2003.03697.x
Date:
26-Apr-03     Release date:   01-Jul-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
297 a.a.*
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
258 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.2.7.11.22  - Cyclin-dependent 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     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   30 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
DOI no: 10.1046/j.1432-1033.2003.03697.x Eur J Biochem 270:3174-3181 (2003)
PubMed id: 12869192  
 
 
Alternative binding modes of an inhibitor to two different kinases.
E.De Moliner, N.R.Brown, L.N.Johnson.
 
  ABSTRACT  
 
Protein kinases are targets for therapeutic agents designed to intervene in signaling processes in the diseased state. Most kinase inhibitors are directed towards the conserved ATP binding site. Because the essential features of this site are conserved in all eukaryotic protein kinases, it is generally assumed that the same compound will bind in a similar manner to different protein kinases. The inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) is a selective inhibitor for the protein kinase CK2 (IC50 1.6 micro m) (Sarno et al. (2001) FEBS Letts.496, 44-48). Three other kinases [cyclin-dependent protein kinase 2 (CDK2), phosphorylase kinase and glycogen synthase kinase 3beta] exhibit approximately 10-fold weaker affinity for TBB than CK2. We report the crystal structure of TBB in complex with phospho-CDK2-cyclin A at 2.2 A resolution and compare the interactions with those observed for TBB bound to CK2. TBB binds at the ATP binding site of both kinases. In CDK2, each of the four bromine atoms makes polar contacts either to main chain oxygens in the hinge region of the kinase or to water molecules, in addition to several van der Waals contacts. The mode of binding of TBB to CDK2 is different from that to CK2. TBB in CDK2 is displaced more towards the hinge region between the N- and C-terminal lobes and rotated relative to TBB in CK2. The ATP binding pocket is wider in CDK2 than in CK2 resulting in fewer van der Waals contacts but TBB in CK2 does not contact the hinge. The structures show that, despite the conservation of the ATP binding pocket, the inhibitor is able to exploit different recognition features so that the same compound can bind in different ways to the two different kinases.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. TBB binding to pCDK2–cyclin A.(A) Schematic representation of the structure of pCDK2 (yellow) and cyclin A (magenta) in complex with TBB (carbon atoms, green; nitrogen atoms, blue; and bromine atoms, cyan). TBB binds at the ATP binding site in the region between the N- and C-terminal lobes and makes contacts with residues in the hinge region. (B) Details of TBB fit to the final sigmaa weighted 2Fo-Fc electron density map. The map is contoured at levels corresponding to 1 (blue contours) and 4 (red contours). The position of ATP is shown superimposed (carbon atoms: black). These figures and those in Fig. 2 Go-were prepared with aesop (M. E. M. Noble, unpublished work).
Figure 2.
Fig. 2. Details of the interactions of TBB with pCDK2 and CK2. Polar contacts to the bromine atoms and hydrogen bonds from nitrogen atoms are shown as black dashed lines. (A) Stereo diagram of TBB bound to pCDK2 (pCDK2 carbon atoms are yellow, TBB carbon atoms are green, TBB bromine atoms are cyan). Ala144 is shown for reference although it does not make any van der Waals interactions with TBB. (B) Stereo diagram of TBB bound to CK2 (CK2 carbon atoms of residues in contact with TBB are orange, CK2 hinge region carbon atoms, which do not contact TBB, are white, TBB carbon atoms are dark green, TBB bromine atoms are magenta). (C) Superposition of TBB bound to pCDK2 (carbon atoms, green; bromine atoms, cyan) and TBB bound to CK2 (carbon atoms, dark green; bromine atoms, magenta). There is a shift of about 2.5 Å and a rotation of about 30° between the two TBB molecules.
 
  The above figures are reprinted by permission from the Federation of European Biochemical Societies: Eur J Biochem (2003, 270, 3174-3181) copyright 2003.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21276931 S.K.Grant, and E.A.Lunney (2011).
Kinase inhibition that hinges on halogen bonds.
  Chem Biol, 18, 3-4.  
19526464 G.Cozza, A.Bortolato, and S.Moro (2010).
How druggable is protein kinase CK2?
  Med Res Rev, 30, 419-462.  
20649334 H.Torii (2010).
Intermolecular charge flux as the origin of infrared intensity enhancement upon halogen-bond formation of the peptide group.
  J Chem Phys, 133, 034504.  
19821123 N.Zhang, and R.Zhong (2010).
Structural basis for decreased affinity of Emodin binding to Val66-mutated human CK2 alpha as determined by molecular dynamics.
  J Mol Model, 16, 771-780.  
20851342 S.Baumli, J.A.Endicott, and L.N.Johnson (2010).
Halogen bonds form the basis for selective P-TEFb inhibition by DRB.
  Chem Biol, 17, 931-936.
PDB codes: 3my1 3my5
20428531 Y.Lu, Y.Wang, and W.Zhu (2010).
Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design.
  Phys Chem Chem Phys, 12, 4543-4551.  
18267130 B.D.Marsden, and S.Knapp (2008).
Doing more than just the structure-structural genomics in kinase drug discovery.
  Curr Opin Chem Biol, 12, 40-45.  
19032760 D.R.Caffrey, E.A.Lunney, and D.J.Moshinsky (2008).
Prediction of specificity-determining residues for small-molecule kinase inhibitors.
  BMC Bioinformatics, 9, 491.  
17013631 P.Politzer, P.Lane, M.C.Concha, Y.Ma, and J.S.Murray (2007).
An overview of halogen bonding.
  J Mol Model, 13, 305-311.  
17768728 R.Battistutta, M.Mazzorana, L.Cendron, A.Bortolato, S.Sarno, Z.Kazimierczuk, G.Zanotti, S.Moro, and L.A.Pinna (2007).
The ATP-binding site of protein kinase CK2 holds a positive electrostatic area and conserved water molecules.
  Chembiochem, 8, 1804-1809.
PDB codes: 2oxd 2oxx 2oxy
16298300 R.Battistutta, M.Mazzorana, S.Sarno, Z.Kazimierczuk, G.Zanotti, and L.A.Pinna (2005).
Inspecting the structure-activity relationship of protein kinase CK2 inhibitors derived from tetrabromo-benzimidazole.
  Chem Biol, 12, 1211-1219.
PDB codes: 1zoe 1zog 1zoh
14996846 M.Gassel, C.B.Breitenlechner, N.König, R.Huber, R.A.Engh, and D.Bossemeyer (2004).
The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A.
  J Biol Chem, 279, 23679-23690.
PDB code: 1szm
15557000 P.Auffinger, F.A.Hays, E.Westhof, and P.S.Ho (2004).
Halogen bonds in biological molecules.
  Proc Natl Acad Sci U S A, 101, 16789-16794.  
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.