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PDBsum entry 2vrx
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protein ligands Protein-protein interface(s) links
Cell cycle/transferase PDB id
2vrx

 

 

 

 

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Contents
Protein chains
269 a.a. *
41 a.a. *
43 a.a. *
Ligands
447 ×2
Waters ×594
* Residue conservation analysis
PDB id:
2vrx
Name: Cell cycle/transferase
Title: Structure of aurora b kinase in complex with zm447439
Structure: Serine/threonine-protein kinase 12-a. Chain: a, b. Fragment: catalytic kinase domain, residues 77-361. Synonym: aurora-b-a, aurora/ipl1-related kinase 2-a, airk2-a, protein kinase. Inner centromere protein a. Chain: c, d. Fragment: residues 798-840. Synonym: mitotic phosphoprotein 130, xl-incenp
Source: Xenopus laevis. African clawed frog. Organism_taxid: 8355. Organism_taxid: 8355
Resolution:
1.86Å     R-factor:   0.191     R-free:   0.243
Authors: F.Girdler,F.Sessa,S.Patercoli,F.Villa,E.Ridgway,A.Musacchio, S.S.Taylor
Key ref: F.Girdler et al. (2008). Molecular basis of drug resistance in aurora kinases. Chem Biol, 15, 552-562. PubMed id: 18559266
Date:
16-Apr-08     Release date:   01-Jul-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q6DE08  (AUKBA_XENLA) -  Aurora kinase B-A from Xenopus laevis
Seq:
Struc: 		361 a.a.
269 a.a.*
Protein chain
Pfam   ArchSchema ?
O13024  (INCEA_XENLA) -  Inner centromere protein A from Xenopus laevis
Seq:
Struc: 		 
Seq:
Struc: 		873 a.a.
41 a.a.
Protein chain
Pfam   ArchSchema ?
O13024  (INCEA_XENLA) -  Inner centromere protein A from Xenopus laevis
Seq:
Struc: 		 
Seq:
Struc: 		873 a.a.
43 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.2.7.11.1  - non-specific serine/threonine 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    
 
 
Chem Biol 15:552-562 (2008)
PubMed id: 18559266  
 
 
Molecular basis of drug resistance in aurora kinases.
F.Girdler, F.Sessa, S.Patercoli, F.Villa, A.Musacchio, S.Taylor.
 
  ABSTRACT  
 
Aurora kinases have emerged as potential targets in cancer therapy, and several drugs are currently undergoing preclinical and clinical validation. Whether clinical resistance to these drugs can arise is unclear. We exploited a hypermutagenic cancer cell line to select mutations conferring resistance to a well-studied Aurora inhibitor, ZM447439. All resistant clones contained dominant point mutations in Aurora B. Three mutations map to residues in the ATP-binding pocket that are distinct from the "gatekeeper" residue. The mutants retain wild-type catalytic activity and were resistant to all of the Aurora inhibitors tested. Our studies predict that drug-resistant Aurora B mutants are likely to arise during clinical treatment. Furthermore, because the plasticity of the ATP-binding pocket renders Aurora B insensitive to multiple inhibitors, our observations indicate that the drug-resistant Aurora B mutants should be exploited as novel drug targets.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20386909 A.M.Traynor, M.Hewitt, G.Liu, K.T.Flaherty, J.Clark, S.J.Freedman, B.B.Scott, A.M.Leighton, P.A.Watson, B.Zhao, P.J.O'Dwyer, and G.Wilding (2011).
Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors.
  Cancer Chemother Pharmacol, 67, 305-314.  
20175926 C.P.Gully, F.Zhang, J.Chen, J.A.Yeung, G.Velazquez-Torres, E.Wang, S.C.Yeung, and M.H.Lee (2010).
Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer.
  Mol Cancer, 9, 42.  
  20044834 R.Krishnamurty, and D.J.Maly (2010).
Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors.
  ACS Chem Biol, 5, 121-138.  
18974773 G.Amabile, A.M.D'Alise, M.Iovino, P.Jones, S.Santaguida, A.Musacchio, S.Taylor, and R.Cortese (2009).
The Aurora B kinase activity is required for the maintenance of the differentiated state of murine myoblasts.
  Cell Death Differ, 16, 321-330.  
19188929 J.Guo, M.G.Anderson, P.Tapang, J.P.Palma, L.E.Rodriguez, A.Niquette, J.Li, J.J.Bouska, G.Wang, D.Semizarov, D.H.Albert, C.K.Donawho, K.B.Glaser, and O.J.Shah (2009).
Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152.
  Pharmacogenomics J, 9, 90.  
19359241 P.J.Scutt, M.L.Chu, D.A.Sloane, M.Cherry, C.R.Bignell, D.H.Williams, and P.A.Eyers (2009).
Discovery and exploitation of inhibitor-resistant aurora and polo kinase mutants for the analysis of mitotic networks.
  J Biol Chem, 284, 15880-15893.  
19568282 S.Lapenna, and A.Giordano (2009).
Cell cycle kinases as therapeutic targets for cancer.
  Nat Rev Drug Discov, 8, 547-566.  
19199284 T.Sardon, T.Cottin, J.Xu, A.Giannis, and I.Vernos (2009).
Development and biological evaluation of a novel aurora A kinase inhibitor.
  Chembiochem, 10, 464-478.  
19951914 Z.Xu, H.Ogawa, P.Vagnarelli, J.H.Bergmann, D.F.Hudson, S.Ruchaud, T.Fukagawa, W.C.Earnshaw, and K.Samejima (2009).
INCENP-aurora B interactions modulate kinase activity and chromosome passenger complex localization.
  J Cell Biol, 187, 637-653.  
18662747 G.Vader, and S.M.Lens (2008).
The Aurora kinase family in cell division and cancer.
  Biochim Biophys Acta, 1786, 60-72.  
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.

 

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