PDBsum entry 2f4j

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Transferase PDB id
Protein chain
287 a.a. *
Waters ×211
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of the kinase domain of an imatinib-resistant abl mutant in complex with the aurora kinase inhibitor vx-680
Structure: Proto-oncogene tyrosine-protein kinase abl1. Chain: a. Fragment: kinase domain, residues 227-513. Synonym: p150, c- abl. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: abl1, abl, jtk7. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.91Å     R-factor:   0.207     R-free:   0.239
Authors: M.A.Young,N.P.Shah,L.H.Chao,P.Zarrinkar,P.Sawyers,J.Kuriyan
Key ref: M.A.Young et al. (2006). Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res, 66, 1007-1014. PubMed id: 16424036 DOI: 10.1158/0008-5472.CAN-05-2788
23-Nov-05     Release date:   24-Jan-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1
1130 a.a.
287 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [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  


DOI no: 10.1158/0008-5472.CAN-05-2788 Cancer Res 66:1007-1014 (2006)
PubMed id: 16424036  
Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.
M.A.Young, N.P.Shah, L.H.Chao, M.Seeliger, Z.V.Milanov, W.H.Biggs, D.K.Treiber, H.K.Patel, P.P.Zarrinkar, D.J.Lockhart, C.L.Sawyers, J.Kuriyan.
We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His(396)Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21327563 F.P.Santos, and A.Quintás-Cardama (2011).
New drugs for chronic myelogenous leukemia.
  Curr Hematol Malig Rep, 6, 96.  
21264348 R.E.Iacob, J.Zhang, N.S.Gray, and J.R.Engen (2011).
Allosteric interactions between the myristate- and ATP-site of the Abl kinase.
  PLoS One, 6, e15929.  
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.  
21481795 W.W.Chan, S.C.Wise, M.D.Kaufman, Y.M.Ahn, C.L.Ensinger, T.Haack, M.M.Hood, J.Jones, J.W.Lord, W.P.Lu, D.Miller, W.C.Patt, B.D.Smith, P.A.Petillo, T.J.Rutkoski, H.Telikepalli, L.Vogeti, T.Yao, L.Chun, R.Clark, P.Evangelista, L.C.Gavrilescu, K.Lazarides, V.M.Zaleskas, L.J.Stewart, R.A.Van Etten, and D.L.Flynn (2011).
Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
  Cancer Cell, 19, 556-568.
PDB codes: 3qri 3qrj 3qrk
20165848 A.M.Carella (2010).
Hypothesis: upfront use of ABL kinase inhibitor combination, either simultaneously or sequentially, in high-risk Ph+ leukemias?
  Ann Hematol, 89, 531-533.  
20147976 A.S.Moore, J.Blagg, S.Linardopoulos, and A.D.Pearson (2010).
Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias.
  Leukemia, 24, 671-678.  
20038231 D.J.DeAngelo, and E.C.Attar (2010).
Use of dasatinib and nilotinib in imatinib-resistant chronic myeloid leukemia: translating preclinical findings to clinical practice.
  Leuk Lymphoma, 51, 363-375.  
20519627 D.W.Sherbenou, O.Hantschel, I.Kaupe, S.Willis, T.Bumm, L.P.Turaga, T.Lange, K.H.Dao, R.D.Press, B.J.Druker, G.Superti-Furga, and M.W.Deininger (2010).
BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib.
  Blood, 116, 3278-3285.  
20388735 F.Fei, S.Stoddart, J.Groffen, and N.Heisterkamp (2010).
Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias.
  Mol Cancer Ther, 9, 1318-1327.  
20509136 M.Radi, E.Crespan, F.Falchi, V.Bernardo, S.Zanoli, F.Manetti, S.Schenone, G.Maga, and M.Botta (2010).
Design and synthesis of thiadiazoles and thiazoles targeting the Bcr-Abl T315I mutant: from docking false positives to ATP-noncompetitive inhibitors.
  ChemMedChem, 5, 1226-1231.  
20548094 R.Tanaka, M.S.Squires, S.Kimura, A.Yokota, R.Nagao, T.Yamauchi, M.Takeuchi, H.Yao, M.Reule, T.Smyth, J.F.Lyons, N.T.Thompson, E.Ashihara, O.G.Ottmann, and T.Maekawa (2010).
Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells.
  Blood, 116, 2089-2095.  
20629520 T.Kroll, M.B.Ames, J.A.Pruett, and T.S.Fenske (2010).
Successful management of pregnancy occurring in a patient with chronic myeloid leukemia on dasatinib.
  Leuk Lymphoma, 51, 1751-1753.  
19895503 T.Zhou, L.Commodore, W.S.Huang, Y.Wang, T.K.Sawyer, W.C.Shakespeare, T.Clackson, X.Zhu, and D.C.Dalgarno (2010).
Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.
  Chem Biol Drug Des, 75, 18-28.
PDB codes: 3kf4 3kfa
20001232 W.Stock (2010).
Current treatment options for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
  Leuk Lymphoma, 51, 188-198.  
19714203 A.Dixit, and G.M.Verkhivker (2009).
Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.
  PLoS Comput Biol, 5, e1000487.  
19081671 A.Torkamani, G.Verkhivker, and N.J.Schork (2009).
Cancer driver mutations in protein kinase genes.
  Cancer Lett, 281, 117-127.  
19104514 J.Zhang, P.L.Yang, and N.S.Gray (2009).
Targeting cancer with small molecule kinase inhibitors.
  Nat Rev Cancer, 9, 28-39.  
19039816 M.A.Santucci, V.Corradi, M.Mancini, F.Manetti, M.Radi, S.Schenone, and M.Botta (2009).
C6-unsubstituted pyrazolo[3,4-d]pyrimidines are dual Src/Abl inhibitors effective against imatinib mesylate resistant chronic myeloid leukemia cell lines.
  ChemMedChem, 4, 118-126.  
19343480 M.Yamamoto, K.Kakihana, K.Ohashi, T.Yamaguchi, K.Tadokoro, H.Akiyama, and H.Sakamaki (2009).
Serial monitoring of T315I BCR-ABL mutation by Invader assay combined with RT-PCR.
  Int J Hematol, 89, 482-488.  
19204794 N.L.Komarova, A.A.Katouli, and D.Wodarz (2009).
Combination of two but not three current targeted drugs can improve therapy of chronic myeloid leukemia.
  PLoS ONE, 4, e4423.  
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.  
19210352 S.Salemi, S.Yousefi, D.Simon, I.Schmid, L.Moretti, L.Scapozza, and H.U.Simon (2009).
A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome.
  Allergy, 64, 913-918.  
19109437 Y.Shan, M.A.Seeliger, M.P.Eastwood, F.Frank, H.Xu, M...Jensen, R.O.Dror, J.Kuriyan, and D.E.Shaw (2009).
A conserved protonation-dependent switch controls drug binding in the Abl kinase.
  Proc Natl Acad Sci U S A, 106, 139-144.  
18268096 A.Gontarewicz, S.Balabanov, G.Keller, R.Colombo, A.Graziano, E.Pesenti, D.Benten, C.Bokemeyer, W.Fiedler, J.Moll, and T.H.Brümmendorf (2008).
Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I.
  Blood, 111, 4355-4364.  
18662907 B.Zhao, A.Smallwood, J.Yang, K.Koretke, K.Nurse, A.Calamari, R.B.Kirkpatrick, and Z.Lai (2008).
Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2.
  Protein Sci, 17, 1791-1797.
PDB code: 3e5a
18429956 D.Akahane, T.Tauchi, S.Okabe, K.Nunoda, and K.Ohyashiki (2008).
Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL: in vitro and in vivo studies.
  Cancer Sci, 99, 1251-1257.  
18043265 D.Milojkovic, and J.Apperley (2008).
State-of-the-art in the treatment of chronic myeloid leukaemia.
  Curr Opin Oncol, 20, 112-121.  
18023292 G.Mountzios, E.Terpos, and M.A.Dimopoulos (2008).
Aurora kinases as targets for cancer therapy.
  Cancer Treat Rev, 34, 175-182.  
18395149 J.M.Allan (2008).
The genetics of cancer survivorship.
  Hematol Oncol Clin North Am, 22, 257.  
  18728706 M.Henkes, H.van der Kuip, and W.E.Aulitzky (2008).
Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark).
  Ther Clin Risk Manag, 4, 163-187.  
18759691 R.Tanaka, and S.Kimura (2008).
Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation.
  Expert Rev Anticancer Ther, 8, 1387-1398.  
18536580 S.Larson, and W.Stock (2008).
Progress in the treatment of adults with acute lymphoblastic leukemia.
  Curr Opin Hematol, 15, 400-407.  
18491988 T.O'Hare, C.A.Eide, and M.W.Deininger (2008).
New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check.
  Expert Opin Investig Drugs, 17, 865-878.  
18829489 W.Fiskus, Y.Wang, R.Joshi, R.Rao, Y.Yang, J.Chen, R.Kolhe, R.Balusu, K.Eaton, P.Lee, C.Ustun, A.Jillella, C.A.Buser, S.Peiper, and K.Bhalla (2008).
Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells.
  Clin Cancer Res, 14, 6106-6115.  
18667445 X.B.Wan, Z.J.Long, M.Yan, J.Xu, L.P.Xia, L.Liu, Y.Zhao, X.F.Huang, X.R.Wang, X.F.Zhu, M.H.Hong, and Q.Liu (2008).
Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
  Carcinogenesis, 29, 1930-1937.  
18505786 Y.Dai, S.Chen, C.A.Venditti, X.Y.Pei, T.K.Nguyen, P.Dent, and S.Grant (2008).
Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate.
  Blood, 112, 793-804.  
17853901 A.Quintás-Cardama, H.Kantarjian, and J.Cortes (2007).
Flying under the radar: the new wave of BCR-ABL inhibitors.
  Nat Rev Drug Discov, 6, 834-848.  
17671641 D.W.Sherbenou, and B.J.Druker (2007).
Applying the discovery of the Philadelphia chromosome.
  J Clin Invest, 117, 2067-2074.  
18032972 E.Jabbour, J.Cortes, F.Giles, and H.Kantarjian (2007).
Current perspectives on the treatment of patients with chronic myeloid leukemia: an individualized approach to treatment.
  Cancer J, 13, 357-365.  
17240048 G.M.Cheetham, P.A.Charlton, J.M.Golec, and J.R.Pollard (2007).
Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680.
  Cancer Lett, 251, 323-329.  
17167796 G.M.Verkhivker (2007).
In silico profiling of tyrosine kinases binding specificity and drug resistance using Monte Carlo simulations with the ensembles of protein kinase crystal structures.
  Biopolymers, 85, 333-348.  
17173284 G.M.Verkhivker (2007).
Computational proteomics of biomolecular interactions in the sequence and structure space of the tyrosine kinome: deciphering the molecular basis of the kinase inhibitors selectivity.
  Proteins, 66, 912-929.  
17537753 G.M.Verkhivker (2007).
Exploring sequence-structure relationships in the tyrosine kinome space: functional classification of the binding specificity mechanisms for cancer therapeutics.
  Bioinformatics, 23, 1919-1926.  
18067005 L.Kujawski, and M.Talpaz (2007).
Strategies for overcoming imatinib resistance in chronic myeloid leukemia.
  Leuk Lymphoma, 48, 2310-2322.  
17355866 M.A.Seeliger, B.Nagar, F.Frank, X.Cao, M.N.Henderson, and J.Kuriyan (2007).
c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty.
  Structure, 15, 299-311.
PDB code: 2oiq
17710227 N.P.Shah, B.J.Skaggs, S.Branford, T.P.Hughes, J.M.Nicoll, R.L.Paquette, and C.L.Sawyers (2007).
Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency.
  J Clin Invest, 117, 2562-2569.  
17662883 R.Hehlmann, A.Hochhaus, and M.Baccarani (2007).
Chronic myeloid leukaemia.
  Lancet, 370, 342-350.  
18205699 S.Li, and D.Li (2007).
Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors.
  J Cell Mol Med, 11, 1251-1262.  
17164530 S.W.Cowan-Jacob, G.Fendrich, A.Floersheimer, P.Furet, J.Liebetanz, G.Rummel, P.Rheinberger, M.Centeleghe, D.Fabbro, and P.W.Manley (2007).
Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.
  Acta Crystallogr D Biol Crystallogr, 63, 80-93.
PDB codes: 2hyy 2hz0 2hz4 2hzi 2hzn
17671637 T.Hunter (2007).
Treatment for chronic myelogenous leukemia: the long road to imatinib.
  J Clin Invest, 117, 2036-2043.  
17218385 T.K.Nguyen, M.Rahmani, H.Harada, P.Dent, and S.Grant (2007).
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
  Blood, 109, 4006-4015.  
17929114 T.Maekawa, E.Ashihara, and S.Kimura (2007).
The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias.
  Int J Clin Oncol, 12, 327-340.  
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
17355221 Y.Alvarado, E.Apostolidou, R.Swords, and F.J.Giles (2007).
Emerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia.
  Expert Opin Emerg Drugs, 12, 165-179.  
16645167 E.Lierman, C.Folens, E.H.Stover, N.Mentens, H.Van Miegroet, W.Scheers, M.Boogaerts, P.Vandenberghe, P.Marynen, and J.Cools (2006).
Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant.
  Blood, 108, 1374-1376.  
16721384 F.J.Giles (2006).
Clone wars in CML.
  Leukemia, 20, 939-940.  
17064224 M.Bocchia, F.Forconi, and F.Lauria (2006).
Emerging drugs in chronic myelogenous leukaemia.
  Expert Opin Emerg Drugs, 11, 651-664.  
16640460 N.M.Levinson, O.Kuchment, K.Shen, M.A.Young, M.Koldobskiy, M.Karplus, P.A.Cole, and J.Kuriyan (2006).
A Src-like inactive conformation in the abl tyrosine kinase domain.
  PLoS Biol, 4, e144.
PDB codes: 2g1t 2g2f 2g2h 2g2i
17108975 T.K.Sawyer (2006).
Smart drug discovery leveraging innovative technologies and predictive knowledge.
  Nat Chem Biol, 2, 646-648.  
17005277 T.L.Sorensen, K.E.McAuley, R.Flaig, and E.M.Duke (2006).
New light for science: synchrotron radiation in structural medicine.
  Trends Biotechnol, 24, 500-508.  
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.