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PDBsum entry 2g1t
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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2g1t

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
271 a.a. *
Ligands
GLU-ILE-PHE-GLY-
GLU-PHE-GLU-ALA
GLU-GLU-ILE-PHE-
GLY-GLU-PHE-GLU-
ALA-LYS
GLU-ILE-PHE-GLY-
GLU-PHE-GLU
GLU-GLU-ILE-PHE-
GLY-GLU-PHE-GLU
112 ×4
Metals
_MG ×4
Waters ×899
* Residue conservation analysis
PDB id:
2g1t
Name: Transferase
Title: A src-like inactive conformation in the abl tyrosine kinase domain
Structure: Proto-oncogene tyrosine-protein kinase abl1. Chain: a, b, c, d. Fragment: kinase domain. Synonym: p150, c- abl, abelson murine leukemia viral oncogene homolog 1. Engineered: yes. Atp-peptide conjugate. Chain: e, f, g, h. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: abl1, abl, jtk7. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: solid phase peptide synthesis
Biol. unit: Dimer (from PQS)
Resolution:
1.80Å     R-factor:   0.219     R-free:   0.244
Authors: N.M.Levinson,O.Kuchment
Key ref: N.M.Levinson et al. (2006). A Src-like inactive conformation in the abl tyrosine kinase domain. Plos Biol, 4, e144-767. PubMed id: 16640460
Date:
14-Feb-06     Release date:   23-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1130 a.a.
271 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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]
Bound ligand (Het Group name = 112)
matches with 83.33% similarity 		+ ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
Plos Biol 4:e144-767 (2006)
PubMed id: 16640460  
 
 
A Src-like inactive conformation in the abl tyrosine kinase domain.
N.M.Levinson, O.Kuchment, K.Shen, M.A.Young, M.Koldobskiy, M.Karplus, P.A.Cole, J.Kuriyan.
 
  ABSTRACT  
 
The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22504184 C.C.Smith, Q.Wang, C.S.Chin, S.Salerno, L.E.Damon, M.J.Levis, A.E.Perl, K.J.Travers, S.Wang, J.P.Hunt, P.P.Zarrinkar, E.E.Schadt, A.Kasarskis, J.Kuriyan, and N.P.Shah (2012).
Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.
  Nature, 485, 260-263.  
21444691 A.Chawla, S.Chakrabarti, G.Ghosh, and M.Niwa (2011).
Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase.
  J Cell Biol, 193, 41-50.  
21173975 L.De Vico, M.H.Sørensen, L.Iversen, D.M.Rogers, B.S.Sørensen, M.Brandbyge, J.Nygård, K.L.Martinez, and J.H.Jensen (2011).
Quantifying signal changes in nano-wire based biosensors.
  Nanoscale, 3, 706-717.  
21347248 M.Preyer, P.Vigneri, and J.Y.Wang (2011).
Interplay between Kinase Domain Autophosphorylation and F-Actin Binding Domain in Regulating Imatinib Sensitivity and Nuclear Import of BCR-ABL.
  PLoS One, 6, e17020.  
21474065 N.Jura, X.Zhang, N.F.Endres, M.A.Seeliger, T.Schindler, and J.Kuriyan (2011).
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
  Mol Cell, 42, 9.  
22101934 Z.Wang, P.A.Longo, M.K.Tarrant, K.Kim, S.Head, D.J.Leahy, and P.A.Cole (2011).
Mechanistic insights into the activation of oncogenic forms of EGF receptor.
  Nat Struct Mol Biol, 18, 1388-1393.  
20141838 B.Yu, I.R.Martins, P.Li, G.K.Amarasinghe, J.Umetani, M.E.Fernandez-Zapico, D.D.Billadeau, M.Machius, D.R.Tomchick, and M.K.Rosen (2010).
Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1.
  Cell, 140, 246-256.
PDB code: 3ky9
19774589 D.Lavogina, E.Enkvist, and A.Uri (2010).
Bisubstrate inhibitors of protein kinases: from principle to practical applications.
  ChemMedChem, 5, 23-34.  
19965870 J.M.Steichen, G.H.Iyer, S.Li, S.A.Saldanha, M.S.Deal, V.L.Woods, and S.S.Taylor (2010).
Global consequences of activation loop phosphorylation on protein kinase A.
  J Biol Chem, 285, 3825-3832.  
20626563 J.P.Covy, and B.I.Giasson (2010).
The G2019S pathogenic mutation disrupts sensitivity of leucine-rich repeat kinase 2 to manganese kinase inhibition.
  J Neurochem, 115, 36-46.  
20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
19173306 A.Papakyriakou, D.Vourloumis, F.Tzortzatou-Stathopoulou, and M.Karpusas (2009).
Conformational dynamics of the EGFR kinase domain reveals structural features involved in activation.
  Proteins, 76, 375-386.  
18827185 A.Quintás-Cardama, and J.Cortes (2009).
Molecular biology of bcr-abl1-positive chronic myeloid leukemia.
  Blood, 113, 1619-1630.  
19081671 A.Torkamani, G.Verkhivker, and N.J.Schork (2009).
Cancer driver mutations in protein kinase genes.
  Cancer Lett, 281, 117-127.  
19204278 C.Hyeon, P.A.Jennings, J.A.Adams, and J.N.Onuchic (2009).
Ligand-induced global transitions in the catalytic domain of protein kinase A.
  Proc Natl Acad Sci U S A, 106, 3023-3028.  
19518076 C.Qiu, M.K.Tarrant, T.Boronina, P.A.Longo, J.M.Kavran, R.N.Cole, P.A.Cole, and D.J.Leahy (2009).
In vitro enzymatic characterization of near full length EGFR in activated and inhibited states.
  Biochemistry, 48, 6624-6632.  
19224897 E.D.Lew, C.M.Furdui, K.S.Anderson, and J.Schlessinger (2009).
The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations.
  Sci Signal, 2, ra6.  
19326384 F.Falchi, F.Manetti, F.Carraro, A.Naldini, G.Maga, E.Crespan, S.Schenone, O.Bruno, C.Brullo, and M.Botta (2009).
3D QSAR models built on structure-based alignments of Abl tyrosine kinase inhibitors.
  ChemMedChem, 4, 976-987.  
20161143 H.Huang, E.Ozkirimli, and C.B.Post (2009).
A Comparison of Three Perturbation Molecular Dynamics Methods for Modeling Conformational Transitions.
  J Chem Theory Comput, 5, 1301-1314.  
19124027 I.Westwood, D.M.Cheary, J.E.Baxter, M.W.Richards, R.L.van Montfort, A.M.Fry, and R.Bayliss (2009).
Insights into the conformational variability and regulation of human Nek2 kinase.
  J Mol Biol, 386, 476-485.
PDB codes: 2w5a 2w5b 2w5h
19396179 J.R.Simard, S.Klüter, C.Grütter, M.Getlik, M.Rabiller, H.B.Rode, and D.Rauh (2009).
A new screening assay for allosteric inhibitors of cSrc.
  Nat Chem Biol, 5, 394-396.
PDB codes: 3f3t 3f3u
19276351 M.A.Seeliger, P.Ranjitkar, C.Kasap, Y.Shan, D.E.Shaw, N.P.Shah, J.Kuriyan, and D.J.Maly (2009).
Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.
  Cancer Res, 69, 2384-2392.
PDB codes: 3g6g 3g6h
19489734 M.K.Tarrant, and P.A.Cole (2009).
The chemical biology of protein phosphorylation.
  Annu Rev Biochem, 78, 797-825.  
20007378 N.Jura, Y.Shan, X.Cao, D.E.Shaw, and J.Kuriyan (2009).
Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.
  Proc Natl Acad Sci U S A, 106, 21608-21613.
PDB code: 3kex
18761339 R.Bose, and X.Zhang (2009).
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
  Exp Cell Res, 315, 649-658.  
19225111 S.Yang, N.K.Banavali, and B.Roux (2009).
Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories.
  Proc Natl Acad Sci U S A, 106, 3776-3781.  
19703025 V.Kairys, M.K.Gilson, V.Lather, C.A.Schiffer, and M.X.Fernandes (2009).
Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.
  Chem Biol Drug Des, 74, 234-245.  
18940662 A.C.Dar, M.S.Lopez, and K.M.Shokat (2008).
Small molecule recognition of c-Src via the Imatinib-binding conformation.
  Chem Biol, 15, 1015-1022.
PDB codes: 3el7 3el8
18282484 B.E.Turk (2008).
Understanding and exploiting substrate recognition by protein kinases.
  Curr Opin Chem Biol, 12, 4.  
18334220 C.Qiu, M.K.Tarrant, S.H.Choi, A.Sathyamurthy, R.Bose, S.Banjade, A.Pal, W.G.Bornmann, M.A.Lemmon, P.A.Cole, and D.J.Leahy (2008).
Mechanism of activation and inhibition of the HER4/ErbB4 kinase.
  Structure, 16, 460-467.
PDB codes: 3bbt 3bbw 3bce
18687871 E.Ozkirimli, S.S.Yadav, W.T.Miller, and C.B.Post (2008).
An electrostatic network and long-range regulation of Src kinases.
  Protein Sci, 17, 1871-1880.  
18469827 K.Strebhardt, A.Ullrich, and P.Ehrlich (2008).
Paul Ehrlich's magic bullet concept: 100 years of progress.
  Nat Rev Cancer, 8, 473-480.  
18794843 M.Azam, M.A.Seeliger, N.S.Gray, J.Kuriyan, and G.Q.Daley (2008).
Activation of tyrosine kinases by mutation of the gatekeeper threonine.
  Nat Struct Mol Biol, 15, 1109-1118.
PDB codes: 3dqw 3dqx
17910071 M.D.Jacobs, P.R.Caron, and B.J.Hare (2008).
Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
  Proteins, 70, 1451-1460.
PDB code: 2pl0
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.  
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.  
18796434 X.Cao, K.Q.Tanis, A.J.Koleske, and J.Colicelli (2008).
Enhancement of ABL kinase catalytic efficiency by a direct binding regulator is independent of other regulatory mechanisms.
  J Biol Chem, 283, 31401-31407.  
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.  
18059449 D.J.Leahy (2007).
A monkey wrench in the kinase machine.
  Nat Struct Mol Biol, 14, 1120-1121.  
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.  
17173068 H.L.Borges, I.C.Hunton, and J.Y.Wang (2007).
Reduction of apoptosis in Rb-deficient embryos via Abl knockout.
  Oncogene, 26, 3868-3877.  
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
18068628 S.Fröhling, C.Scholl, R.L.Levine, M.Loriaux, T.J.Boggon, O.A.Bernard, R.Berger, H.Döhner, K.Döhner, B.L.Ebert, S.Teckie, T.R.Golub, J.Jiang, M.M.Schittenhelm, B.H.Lee, J.D.Griffin, R.M.Stone, M.C.Heinrich, M.W.Deininger, B.J.Druker, and D.G.Gilliland (2007).
Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.
  Cancer Cell, 12, 501-513.  
17095602 A.P.Kornev, N.M.Haste, S.S.Taylor, and L.F.Eyck (2006).
Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism.
  Proc Natl Acad Sci U S A, 103, 17783-17788.  
17114285 M.A.Emrick, T.Lee, P.J.Starkey, M.C.Mumby, K.A.Resing, and N.G.Ahn (2006).
The gatekeeper residue controls autoactivation of ERK2 via a pathway of intramolecular connectivity.
  Proc Natl Acad Sci U S A, 103, 18101-18106.  
17079130 P.Pellicena, and J.Kuriyan (2006).
Protein-protein interactions in the allosteric regulation of protein kinases.
  Curr Opin Struct Biol, 16, 702-709.  
17085043 R.Bose, M.A.Holbert, K.A.Pickin, and P.A.Cole (2006).
Protein tyrosine kinase-substrate interactions.
  Curr Opin Struct Biol, 16, 668-675.  
16777603 X.Zhang, J.Gureasko, K.Shen, P.A.Cole, and J.Kuriyan (2006).
An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.
  Cell, 125, 1137-1149.
PDB codes: 2gs2 2gs6 2gs7
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.

 

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