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PDBsum entry 2qoh
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protein ligands Protein-protein interface(s) links
Transferase PDB id
2qoh

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
271 a.a. *
Ligands
P3Y ×2
Waters ×257
* Residue conservation analysis
PDB id:
2qoh
Name: Transferase
Title: Crystal structure of abl kinase bound with ppy-a
Structure: Proto-oncogene tyrosine-protein kinase abl1. Chain: a, b. Fragment: residues 228-515. Synonym: p150, c-abl, abelson murine leukemia viral oncogene homolog 1, abl kinase. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.95Å     R-factor:   0.214     R-free:   0.255
Authors: T.Zhou,D.Dalgarno,X.Zhu
Key ref: T.Zhou et al. (2007). Crystal structure of the T315I mutant of AbI kinase. Chem Biol Drug Des, 70, 171-181. PubMed id: 17718712
Date:
20-Jul-07     Release date:   18-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00520  (ABL1_MOUSE) -  Tyrosine-protein kinase ABL1 from Mus musculus
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1123 a.a.
271 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.2.7.10.2  - non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
Chem Biol Drug Des 70:171-181 (2007)
PubMed id: 17718712  
 
 
Crystal structure of the T315I mutant of AbI kinase.
T.Zhou, L.Parillon, F.Li, Y.Wang, J.Keats, S.Lamore, Q.Xu, W.Shakespeare, D.Dalgarno, X.Zhu.
 
  ABSTRACT  
 
Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr-AbI. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr-AbI inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib-resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c-AbI T315I mutant, as well as the wild-type form, in complex with a pyrrolopyridine inhibitor, PPY-A. The side chain of Ile315 is accommodated in the AbI T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY-A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine-rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr-AbI T315I.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
21118377 T.Zhou, L.Commodore, W.S.Huang, Y.Wang, M.Thomas, J.Keats, Q.Xu, V.M.Rivera, W.C.Shakespeare, T.Clackson, D.C.Dalgarno, and X.Zhu (2011).
Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance.
  Chem Biol Drug Des, 77, 1.
PDB codes: 3oxz 3oy3
20808800 A.A.Katouli, and N.L.Komarova (2010).
Optimizing combination therapies with existing and future CML drugs.
  PLoS One, 5, e12300.  
20299508 E.Weisberg, H.G.Choi, A.Ray, R.Barrett, J.Zhang, T.Sim, W.Zhou, M.Seeliger, M.Cameron, M.Azam, J.A.Fletcher, M.Debiec-Rychter, M.Mayeda, D.Moreno, A.L.Kung, P.A.Janne, R.Khosravi-Far, J.V.Melo, P.W.Manley, S.Adamia, C.Wu, N.Gray, and J.D.Griffin (2010).
Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.
  Blood, 115, 4206-4216.
PDB code: 4agw
20508612 E.Weisberg, X.Deng, H.G.Choi, R.Barrett, S.Adamia, A.Ray, D.Moreno, A.L.Kung, N.Gray, and J.D.Griffin (2010).
Beneficial effects of combining a type II ATP competitive inhibitor with an allosteric competitive inhibitor of BCR-ABL for the treatment of imatinib-sensitive and imatinib-resistant CML.
  Leukemia, 24, 1375-1378.  
20028401 M.Azam, J.T.Powers, W.Einhorn, W.S.Huang, W.C.Shakespeare, X.Zhu, D.Dalgarno, T.Clackson, T.K.Sawyer, and G.Q.Daley (2010).
AP24163 inhibits the gatekeeper mutant of BCR-ABL and suppresses in vitro resistance.
  Chem Biol Drug Des, 75, 223-227.  
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.  
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
19186126 A.Dixit, A.Torkamani, N.J.Schork, and G.Verkhivker (2009).
Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability.
  Biophys J, 96, 858-874.  
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.  
19834613 A.Dixit, L.Yi, R.Gowthaman, A.Torkamani, N.J.Schork, and G.M.Verkhivker (2009).
Sequence and structure signatures of cancer mutation hotspots in protein kinases.
  PLoS One, 4, e7485.  
19220318 A.G.Villaseñor, R.Kondru, H.Ho, S.Wang, E.Papp, D.Shaw, J.W.Barnett, M.F.Browner, and A.Kuglstatter (2009).
Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes.
  Chem Biol Drug Des, 73, 466-470.
PDB codes: 3fqe 3fqh 3fqs
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.  
19164557 K.S.Gajiwala, J.C.Wu, J.Christensen, G.D.Deshmukh, W.Diehl, J.P.DiNitto, J.M.English, M.J.Greig, Y.A.He, S.L.Jacques, E.A.Lunney, M.McTigue, D.Molina, T.Quenzer, P.A.Wells, X.Yu, Y.Zhang, A.Zou, M.R.Emmett, A.G.Marshall, H.M.Zhang, and G.D.Demetri (2009).
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
  Proc Natl Acad Sci U S A, 106, 1542-1547.
PDB codes: 3g0e 3g0f
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.  
19878872 T.O'Hare, W.C.Shakespeare, X.Zhu, C.A.Eide, V.M.Rivera, F.Wang, L.T.Adrian, T.Zhou, W.S.Huang, Q.Xu, C.A.Metcalf, J.W.Tyner, M.M.Loriaux, A.S.Corbin, S.Wardwell, Y.Ning, J.A.Keats, Y.Wang, R.Sundaramoorthi, M.Thomas, D.Zhou, J.Snodgrass, L.Commodore, T.K.Sawyer, D.C.Dalgarno, M.W.Deininger, B.J.Druker, and T.Clackson (2009).
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
  Cancer Cell, 16, 401-412.
PDB code: 3ik3
18972468 C.Peifer, and D.R.Alessi (2008).
Small-molecule inhibitors of PDK1.
  ChemMedChem, 3, 1810-1838.  
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.  
18367669 T.O'Hare, C.A.Eide, J.W.Tyner, A.S.Corbin, M.J.Wong, S.Buchanan, K.Holme, K.A.Jessen, C.Tang, H.A.Lewis, R.D.Romero, S.K.Burley, and M.W.Deininger (2008).
SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib.
  Proc Natl Acad Sci U S A, 105, 5507-5512.  
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.

 

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