spacer
spacer

PDBsum entry 2hzn

Go to PDB code: 
protein ligands links
Transferase PDB id
2hzn
Jmol
Contents
Protein chain
273 a.a. *
Ligands
KIN
* Residue conservation analysis
PDB id:
2hzn
Name: Transferase
Title: Abl kinase domain in complex with nvp-afg210
Structure: Proto-oncogene tyrosine-protein kinase abl1. Chain: a. Synonym: p150, c-abl, abelson murine leukemia viral oncogen 1. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: abl1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.70Å     R-factor:   0.267     R-free:   0.314
Authors: S.W.Cowan-Jacob,G.Fendrich,J.Liebetanz,D.Fabbro,P.Manley
Key ref:
S.W.Cowan-Jacob et al. (2007). Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr, 63, 80-93. PubMed id: 17164530 DOI: 10.1107/S0907444906047287
Date:
09-Aug-06     Release date:   16-Jan-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00520  (ABL1_MOUSE) -  Tyrosine-protein kinase ABL1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1123 a.a.
273 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1107/S0907444906047287 Acta Crystallogr D Biol Crystallogr 63:80-93 (2007)
PubMed id: 17164530  
 
 
Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.
S.W.Cowan-Jacob, G.Fendrich, A.Floersheimer, P.Furet, J.Liebetanz, G.Rummel, P.Rheinberger, M.Centeleghe, D.Fabbro, P.W.Manley.
 
  ABSTRACT  
 
Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.
 
  Selected figure(s)  
 
Figure 4.
Figure 4 (a) Superposition of the four main DFG conformations observed in Abl kinase structures, with the active conformation in cyan, the DFG-out conformation in yellow, the DFG-flip conformation in grey and the Src-like inactive conformation in green. (b) Superposition of all structures reported here plus PDB entry 2g1t . The P-loop is shown in red, the C-helix is cyan, the A-loop is blue and all the ligands are shown in green. The superposition is based on an alignment of the C-terminal lobes to emphasize the relative differences in angles between the N- and C-terminal lobes of the kinase. (c) A stereoview of all the ligands superimposed (imatinib, magenta C atoms; NVP-AFN941, cyan C atoms; NVP-AFG210, yellow C atoms; NVP-AEG082, green C atoms; PD180970, grey C atoms).
Figure 6.
Figure 6 Comparison of the surfaces for all five structures reported here. The inhibitor is shown with solid sticks (C, yellow; N, blue; O, red; Cl, green; F, cyan) and the solvent-accessible surface is coloured according to the atom type that forms it (C, white; N, blue; O, red; S, orange). The surface is transparent to show the buried parts of the binding site, which are darker for the same reason. The C^ trace of the protein is shown with white lines. (a) Imatinib, (b) NVP-AFN941, (c) PD180970, (d) NVP-AEG082, (e) NVP-AFG210.
 
  The above figures are reprinted from an Open Access publication published by the IUCr: Acta Crystallogr D Biol Crystallogr (2007, 63, 80-93) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19714578 S.Schenone, O.Bruno, M.Radi, and M.Botta (2011).
New insights into small-molecule inhibitors of Bcr-Abl.
  Med Res Rev, 31, 1.  
19924121 C.Tanaka, O.Q.Yin, V.Sethuraman, T.Smith, X.Wang, K.Grouss, H.Kantarjian, F.Giles, O.G.Ottmann, L.Galitz, and H.Schran (2010).
Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib.
  Clin Pharmacol Ther, 87, 197-203.  
20183853 D.D.Robinson, W.Sherman, and R.Farid (2010).
Understanding kinase selectivity through energetic analysis of binding site waters.
  ChemMedChem, 5, 618-627.  
20336234 O.A.Gani, and R.A.Engh (2010).
Protein kinase inhibition of clinically important staurosporine analogues.
  Nat Prod Rep, 27, 489-498.  
20382995 P.Roversi, S.Johnson, and S.M.Lea (2010).
With phases: how two wrongs can sometimes make a right.
  Acta Crystallogr D Biol Crystallogr, 66, 420-425.  
  20044834 R.Krishnamurty, and D.J.Maly (2010).
Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors.
  ACS Chem Biol, 5, 121-138.  
20835477 S.Lü, Q.Luo, X.Li, J.Wu, J.Liu, S.Xiong, Y.Q.Feng, and F.Wang (2010).
Inhibitor screening of protein kinases using MALDI-TOF MS combined with separation and enrichment of phosphopeptides by TiO2 nanoparticle deposited capillary column.
  Analyst, 135, 2858-2863.  
20043185 U.Hinz, R.Apweiler, M.J.Martin, C.O'Donovan, M.Magrane, Y.Alam-Faruque, R.Antunes, D.Barrell, B.Bely, M.Bingley, D.Binns, L.Bower, P.Browne, W.M.Chan, E.Dimmer, R.Eberhardt, A.Fedotov, R.Foulger, J.Garavelli, R.Huntley, J.Jacobsen, M.Kleen, K.Laiho, R.Leinonen, D.Legge, Q.Lin, W.Liu, J.Luo, S.Orchard, S.Patient, D.Poggioli, M.Pruess, M.Corbett, G.di Martino, M.Donnelly, P.van Rensburg, A.Bairoch, L.Bougueleret, I.Xenarios, S.Altairac, A.Auchincloss, G.Argoud-Puy, K.Axelsen, D.Baratin, M.C.Blatter, B.Boeckmann, J.Bolleman, L.Bollondi, E.Boutet, S.B.Quintaje, L.Breuza, A.Bridge, E.de Castro, L.Ciapina, D.Coral, E.Coudert, I.Cusin, F.David, G.Delbard, M.Doche, D.Dornevil, P.D.Roggli, S.Duvaud, A.Estreicher, L.Famiglietti, M.Feuermann, S.Gehant, N.Farriol-Mathis, S.Ferro, E.Gasteiger, A.Gateau, V.Gerritsen, A.Gos, N.Gruaz-Gumowski, U.Hinz, C.Hulo, N.Hulo, J.James, S.Jimenez, F.Jungo, T.Kappler, G.Keller, C.Lachaize, L.Lane-Guermonprez, P.Langendijk-Genevaux, V.Lara, P.Lemercier, D.Lieberherr, T.d.e. .O.Lima, V.Mangold, X.Martin, P.Masson, M.Moinat, A.Morgat, A.Mottaz, S.Paesano, I.Pedruzzi, S.Pilbout, V.Pillet, and S.Poux (2010).
From protein sequences to 3D-structures and beyond: the example of the UniProt knowledgebase.
  Cell Mol Life Sci, 67, 1049-1064.  
20966921 W.Pao, and J.Chmielecki (2010).
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.
  Nat Rev Cancer, 10, 760-774.  
19236722 J.A.Winger, O.Hantschel, G.Superti-Furga, and J.Kuriyan (2009).
The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2).
  BMC Struct Biol, 9, 7.
PDB code: 3fw1
20041122 L.J.Yang, J.Zou, H.Z.Xie, L.L.Li, Y.Q.Wei, and S.Y.Yang (2009).
Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl.
  PLoS One, 4, e8470.  
19150426 R.Barouch-Bentov, J.Che, C.C.Lee, Y.Yang, A.Herman, Y.Jia, A.Velentza, J.Watson, L.Sternberg, S.Kim, N.Ziaee, A.Miller, C.Jackson, M.Fujimoto, M.Young, S.Batalov, Y.Liu, M.Warmuth, T.Wiltshire, M.P.Cooke, and K.Sauer (2009).
A conserved salt bridge in the G loop of multiple protein kinases is important for catalysis and for in vivo Lyn function.
  Mol Cell, 33, 43-52.  
19909299 Y.Asses, V.Leroux, S.Tairi-Kellou, R.Dono, F.Maina, and B.Maigret (2009).
Analysis of c-Met kinase domain complexes: a new specific catalytic site receptor model for defining binding modes of ATP-competitive ligands.
  Chem Biol Drug Des, 74, 560-570.  
18729261 C.Kunick, and A.M.Egert-Schmidt (2008).
[The short history of protein kinase inhibitors. New, competitive, successful]
  Pharm Unserer Zeit, 37, 360-368.  
18820131 E.Weisberg, J.Roesel, G.Bold, P.Furet, J.Jiang, J.Cools, R.D.Wright, E.Nelson, R.Barrett, A.Ray, D.Moreno, E.Hall-Meyers, R.Stone, I.Galinsky, E.Fox, G.Gilliland, J.F.Daley, S.Lazo-Kallanian, A.L.Kung, and J.D.Griffin (2008).
Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells.
  Blood, 112, 5161-5170.  
18711344 L.M.O'Connor, S.Langabeer, S.R.McCann, and E.Conneally (2008).
Restoration of donor chimerism by nilotinib in a chronic myeloid leukaemia patient post mutation-associated imatinib mesylate resistance and allogeneic stem cell transplant failure.
  Bone Marrow Transplant, 42, 833-835.  
18302984 M.Totrov, and R.Abagyan (2008).
Flexible ligand docking to multiple receptor conformations: a practical alternative.
  Curr Opin Struct Biol, 18, 178-184.  
18434310 N.Vajpai, A.Strauss, G.Fendrich, S.W.Cowan-Jacob, P.W.Manley, S.Grzesiek, and W.Jahnke (2008).
Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib.
  J Biol Chem, 283, 18292-18302.  
18566585 S.Baumli, G.Lolli, E.D.Lowe, S.Troiani, L.Rusconi, A.N.Bullock, J.E.Debreczeni, S.Knapp, and L.N.Johnson (2008).
The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation.
  EMBO J, 27, 1907-1918.
PDB codes: 2ivx 3blh 3blq 3blr
18338744 T.S.Lee, S.J.Potts, H.Kantarjian, J.Cortes, F.Giles, and M.Albitar (2008).
Molecular basis explanation for imatinib resistance of BCR-ABL due to T315I and P-loop mutations from molecular dynamics simulations.
  Cancer, 112, 1744-1753.  
18636071 Y.Tanrikulu, and G.Schneider (2008).
Pseudoreceptor models in drug design: bridging ligand- and receptor-based virtual screening.
  Nat Rev Drug Discov, 7, 667-677.  
17715389 H.M.Kantarjian, F.Giles, N.Gattermann, K.Bhalla, G.Alimena, F.Palandri, G.J.Ossenkoppele, F.E.Nicolini, S.G.O'Brien, M.Litzow, R.Bhatia, F.Cervantes, A.Haque, Y.Shou, D.J.Resta, A.Weitzman, A.Hochhaus, and P.le Coutre (2007).
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance.
  Blood, 110, 3540-3546.  
18067005 L.Kujawski, and M.Talpaz (2007).
Strategies for overcoming imatinib resistance in chronic myeloid leukemia.
  Leuk Lymphoma, 48, 2310-2322.  
17671637 T.Hunter (2007).
Treatment for chronic myelogenous leukemia: the long road to imatinib.
  J Clin Invest, 117, 2036-2043.  
17718712 T.Zhou, L.Parillon, F.Li, Y.Wang, J.Keats, S.Lamore, Q.Xu, W.Shakespeare, D.Dalgarno, and X.Zhu (2007).
Crystal structure of the T315I mutant of AbI kinase.
  Chem Biol Drug Des, 70, 171-181.
PDB codes: 2qoh 2z60
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 code is shown on the right.