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PDBsum entry 2fo0

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protein ligands links
Transferase PDB id
2fo0
Jmol
Contents
Protein chain
466 a.a. *
Ligands
MYR
P16
GOL ×2
Waters ×145
* Residue conservation analysis
PDB id:
2fo0
Name: Transferase
Title: Organization of the sh3-sh2 unit in active and inactive form c-abl tyrosine kinase
Structure: Proto-oncogene tyrosine-protein kinase abl1 (1b i chain: a. Fragment: abl n-cap (residues 1-531, residues 15-56 deleted engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: c-abl. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.27Å     R-factor:   0.210     R-free:   0.246
Authors: B.Nagar,O.Hantschel,M.Seeliger,J.M.Davies,W.I.Weis,G.Superti J.Kuriyan
Key ref:
B.Nagar et al. (2006). Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. Mol Cell, 21, 787-798. PubMed id: 16543148 DOI: 10.1016/j.molcel.2006.01.035
Date:
12-Jan-06     Release date:   21-Mar-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1130 a.a.
466 a.a.*
Key:    PfamA domain  PfamB 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: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+
[protein]-L-tyrosine
Bound ligand (Het Group name = MYR)
matches with 45.45% similarity
= 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: 10.1016/j.molcel.2006.01.035 Mol Cell 21:787-798 (2006)
PubMed id: 16543148  
 
 
Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase.
B.Nagar, O.Hantschel, M.Seeliger, J.M.Davies, W.I.Weis, G.Superti-Furga, J.Kuriyan.
 
  ABSTRACT  
 
The tyrosine kinase c-Abl is inactivated by interactions made by its SH3 and SH2 domains with the distal surface of the kinase domain. We present a crystal structure of a fragment of c-Abl which reveals that a critical N-terminal cap segment, not visualized in previous structures, buttresses the SH3-SH2 substructure in the autoinhibited state and locks it onto the distal surface of the kinase domain. Surprisingly, the N-terminal cap is phosphorylated on a serine residue that interacts with the connector between the SH3 and SH2 domains. Small-angle X-ray scattering (SAXS) analysis shows that a mutated form of c-Abl, in which the N-terminal cap and two other key contacts in the autoinhibited state are deleted, exists in an extended array of the SH3, SH2, and kinase domains. This alternative conformation of Abl is likely to prolong the active state of the kinase by preventing it from returning to the autoinhibited state.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Schematic Diagram of the c-Abl Constructs Used and the Structure of the Cap Region
(A) Abl^N-cap was used for both the crystal structure and SAXS analyses. Residues from the N-terminal cap in Abl^N-cap that were deleted are indicated with gray shading, and residues that were included are highlighted in pink.
(B) Surface representation of Abl^N-cap with the cap region shown as a backbone model in pink. Residues that connect the cap to the myristoyl but could not be modeled are shown as pink spheres. Helix αI of the kinase domain is colored purple. A black box indicates the region magnified in (C).
(C) Hydrophobic surface rendition of Abl^N-cap showing cap interactions with the SH2 domain and SH3-SH2 connector. Increasing hydrophobicity of the surface is indicated with darker shades of green. The cap is shown as sticks, where carbon, nitrogen, and oxygen atoms are colored orange, blue, and red, respectively. Labeled are residues that are well ordered and make direct interactions with the protein. The water molecule hydrogen bonded to Lys70 is shown as a blue sphere. Molecular figures were generated with PyMOL (DeLano, 2002).
Figure 4.
Figure 4. Shape Reconstructions
(A) Kinase domain. The backbone of the crystal structure of the c-Abl kinase domain (blue; PDB code 1OPJ) is superimposed onto the shape reconstruction (shown as green mesh).
(B) Abl^N-cap. Superimposed is the crystal structure of Abl^N-cap shown as a green backbone onto the shape reconstruction (gray mesh).
(C) Abl^activated. The kinase domain and SH2 and SH3 domains are colored red, green, and blue, respectively. Indicated on the right view is the part of the model that may correspond to the crystal structure of disassembled c-Abl from the original crystallographic analysis of c-Abl 1b. The SH3 domain was placed by visual inspection, ensuring that its C terminus was in close proximity to the N terminus of the SH2 domain.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 21, 787-798) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21199370 B.R.Groveman, S.Xue, V.Marin, J.Xu, M.K.Ali, E.A.Bienkiewicz, and X.M.Yu (2011).
Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions.
  FEBS J, 278, 643-653.  
21338916 J.Yang, N.Campobasso, M.P.Biju, K.Fisher, X.Q.Pan, J.Cottom, S.Galbraith, T.Ho, H.Zhang, X.Hong, P.Ward, G.Hofmann, B.Siegfried, F.Zappacosta, Y.Washio, P.Cao, J.Qu, S.Bertrand, D.Y.Wang, M.S.Head, H.Li, S.Moores, Z.Lai, K.Johanson, G.Burton, C.Erickson-Miller, G.Simpson, P.Tummino, R.A.Copeland, and A.Oliff (2011).
Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.
  Chem Biol, 18, 177-186.
PDB code: 3pyy
21102429 M.Thai, P.Y.Ting, J.McLaughlin, D.Cheng, M.Müschen, O.N.Witte, and J.Colicelli (2011).
ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1.
  Leukemia, 25, 290-300.  
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.  
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.  
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.  
20841568 J.Colicelli (2010).
ABL tyrosine kinases: evolution of function, regulation, and specificity.
  Sci Signal, 3, re6.  
20357770 J.Wojcik, O.Hantschel, F.Grebien, I.Kaupe, K.L.Bennett, J.Barkinge, R.B.Jones, A.Koide, G.Superti-Furga, and S.Koide (2010).
A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain.
  Nat Struct Mol Biol, 17, 519-527.
PDB code: 3k2m
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.  
19844700 P.Bernadó (2010).
Effect of interdomain dynamics on the structure determination of modular proteins by small-angle scattering.
  Eur Biophys J, 39, 769-780.  
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.  
19926274 P.Filippakopoulos, S.Müller, and S.Knapp (2009).
SH2 domains: modulators of nonreceptor tyrosine kinase activity.
  Curr Opin Struct Biol, 19, 643-649.  
19465916 Q.Yin, S.C.Lin, B.Lamothe, M.Lu, Y.C.Lo, G.Hura, L.Zheng, R.L.Rich, A.D.Campos, D.G.Myszka, M.J.Lenardo, B.G.Darnay, and H.Wu (2009).
E2 interaction and dimerization in the crystal structure of TRAF6.
  Nat Struct Mol Biol, 16, 658-666.
PDB codes: 3hcs 3hct 3hcu
19164531 R.E.Iacob, T.Pene-Dumitrescu, J.Zhang, N.S.Gray, T.E.Smithgall, and J.R.Engen (2009).
Conformational disturbance in Abl kinase upon mutation and deregulation.
  Proc Natl Acad Sci U S A, 106, 1386-1391.  
19290922 R.E.Joseph, and A.H.Andreotti (2009).
Conformational snapshots of Tec kinases during signaling.
  Immunol Rev, 228, 74-92.  
19821459 X.Liao, J.Su, and M.Mrksich (2009).
An adaptor domain-mediated autocatalytic interfacial kinase reaction.
  Chemistry, 15, 12303-12309.  
19679652 Y.Choi, M.A.Seeliger, S.B.Panjarian, H.Kim, X.Deng, T.Sim, B.Couch, A.J.Koleske, T.E.Smithgall, and N.S.Gray (2009).
N-myristoylated c-Abl tyrosine kinase localizes to the endoplasmic reticulum upon binding to an allosteric inhibitor.
  J Biol Chem, 284, 29005-29014.  
18765637 A.S.Oh, J.T.Lahusen, C.D.Chien, M.P.Fereshteh, X.Zhang, S.Dakshanamurthy, J.Xu, B.L.Kagan, A.Wellstein, and A.T.Riegel (2008).
Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells.
  Mol Cell Biol, 28, 6580-6593.  
17934518 B.Perazzona, H.Lin, T.Sun, Y.Wang, and R.Arlinghaus (2008).
Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects.
  Oncogene, 27, 2208-2214.  
18388201 L.M.Rice, E.A.Montabana, and D.A.Agard (2008).
The lattice as allosteric effector: structural studies of alphabeta- and gamma-tubulin clarify the role of GTP in microtubule assembly.
  Proc Natl Acad Sci U S A, 105, 5378-5383.
PDB code: 3cb2
18004789 M.Kosloff, and R.Kolodny (2008).
Sequence-similar, structure-dissimilar protein pairs in the PDB.
  Proteins, 71, 891-902.  
18775312 P.Filippakopoulos, M.Kofler, O.Hantschel, G.D.Gish, F.Grebien, E.Salah, P.Neudecker, L.E.Kay, B.E.Turk, G.Superti-Furga, T.Pawson, and S.Knapp (2008).
Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
  Cell, 134, 793-803.
PDB codes: 3bkb 3cbl 3cd3
18326858 R.R.Iyer, T.J.Pohlhaus, S.Chen, G.L.Hura, L.Dzantiev, L.S.Beese, and P.Modrich (2008).
The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair.
  J Biol Chem, 283, 13310-13319.  
18775435 S.Chen, L.P.O'Reilly, T.E.Smithgall, and J.R.Engen (2008).
Tyrosine phosphorylation in the SH3 domain disrupts negative regulatory interactions within the c-Abl kinase core.
  J Mol Biol, 383, 414-423.  
18452309 S.Chen, T.P.Dumitrescu, T.E.Smithgall, and J.R.Engen (2008).
Abl N-terminal cap stabilization of SH3 domain dynamics.
  Biochemistry, 47, 5795-5803.  
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.  
18328268 X.Xiong, P.Cui, S.Hossain, R.Xu, B.Warner, X.Guo, X.An, A.K.Debnath, D.Cowburn, and L.Kotula (2008).
Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1.
  Biochim Biophys Acta, 1783, 737-747.  
18078545 C.D.Putnam, M.Hammel, G.L.Hura, and J.A.Tainer (2007).
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution.
  Q Rev Biophys, 40, 191-285.  
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.  
17699616 J.D.Faraldo-Gómez, and B.Roux (2007).
On the importance of a funneled energy landscape for the assembly and regulation of multidomain Src tyrosine kinases.
  Proc Natl Acad Sci U S A, 104, 13643-13648.  
17925405 J.Sayegh, K.Webb, D.Cheng, M.T.Bedford, and S.G.Clarke (2007).
Regulation of protein arginine methyltransferase 8 (PRMT8) activity by its N-terminal domain.
  J Biol Chem, 282, 36444-36453.  
17897671 R.E.Joseph, D.B.Fulton, and A.H.Andreotti (2007).
Mechanism and functional significance of Itk autophosphorylation.
  J Mol Biol, 373, 1281-1292.  
17327393 S.Chen, S.Brier, T.E.Smithgall, and J.R.Engen (2007).
The Abl SH2-kinase linker naturally adopts a conformation competent for SH3 domain binding.
  Protein Sci, 16, 572-581.  
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
17574014 T.A.Leonard, and J.H.Hurley (2007).
Two kinase family dramas.
  Cell, 129, 1037-1038.  
17671637 T.Hunter (2007).
Treatment for chronic myelogenous leukemia: the long road to imatinib.
  J Clin Invest, 117, 2036-2043.  
16585765 H.K.Lundgren, and G.R.Björk (2006).
Structural alterations of the cysteine desulfurase IscS of Salmonella enterica serovar Typhimurium reveal substrate specificity of IscS in tRNA thiolation.
  J Bacteriol, 188, 3052-3062.  
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.