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PDBsum entry 1pkg

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protein ligands metals Protein-protein interface(s) links
Transferase activator PDB id
1pkg
Jmol
Contents
Protein chains
292 a.a. *
Ligands
ADP ×2
Metals
_MG ×2
Waters ×3
* Residue conservation analysis
PDB id:
1pkg
Name: Transferase activator
Title: Structure of a c-kit kinase product complex
Structure: C-kit protein. Chain: a, b. Fragment: catalytic domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. (Invitrogen))
Resolution:
2.90Å     R-factor:   0.229     R-free:   0.311
Authors: C.D.Mol,K.B.Lim,V.Sridhar,H.Zou,E.Y.T.Chien,B.-C.Sang,J.Nowa D.B.Kassel,C.N.Cronin,D.E.Mcree
Key ref:
C.D.Mol et al. (2003). Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem, 278, 31461-31464. PubMed id: 12824176 DOI: 10.1074/jbc.C300186200
Date:
05-Jun-03     Release date:   12-Aug-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P10721  (KIT_HUMAN) -  Mast/stem cell growth factor receptor Kit
Seq:
Struc:
 
Seq:
Struc:
976 a.a.
292 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.1  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
=
ADP
Bound ligand (Het Group name = ADP)
corresponds exactly
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.C300186200 J Biol Chem 278:31461-31464 (2003)
PubMed id: 12824176  
 
 
Structure of a c-kit product complex reveals the basis for kinase transactivation.
C.D.Mol, K.B.Lim, V.Sridhar, H.Zou, E.Y.Chien, B.C.Sang, J.Nowakowski, D.B.Kassel, C.N.Cronin, D.E.McRee.
 
  ABSTRACT  
 
The c-Kit proto-oncogene is a receptor protein-tyrosine kinase associated with several highly malignant human cancers. Upon binding its ligand, stem cell factor (SCF), c-Kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. Disease-causing human mutations that activate SCF-independent constitutive expression of c-Kit are found in acute myelogenous leukemia, human mast cell disease, and gastrointestinal stromal tumors. We report on the phosphorylation state and crystal structure of a c-Kit product complex. The c-Kit structure is in a fully active form, with ordered kinase activation and phosphate-binding loops. These results provide key insights into the molecular basis for c-Kit kinase transactivation to assist in the design of new competitive inhibitors targeting activated mutant forms of c-Kit that are resistant to current chemotherapy regimes.
 
  Selected figure(s)  
 
Figure 3.
FIG. 3. Structure of active c-Kit kinase. The C ribbon illustrates the two-domain kinase fold and key structural elements, including the C-helix, phosphate-binding P-loop, adenine-recognition hinge loop, and kinase activation A-loop. The positions of the ADP, metal ion, and substrate peptide are also shown.
Figure 4.
FIG. 4. The c-Kit active site. Interactions at the c-Kit active site with Mg2^+, ADP, and phosphotyrosine are shown.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 31461-31464) copyright 2003.  
  Figures were selected by an automated process.  

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.  
23076159 K.Verstraete, and S.N.Savvides (2012).
Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases.
  Nat Rev Cancer, 12, 753-766.  
22089421 C.L.Corless, C.M.Barnett, and M.C.Heinrich (2011).
Gastrointestinal stromal tumours: origin and molecular oncology.
  Nat Rev Cancer, 11, 865-878.  
21359601 P.M.Chan (2011).
Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model.
  Protein Cell, 2, 108-115.  
20092323 A.Gangjee, N.Zaware, S.Raghavan, M.Ihnat, S.Shenoy, and R.L.Kisliuk (2010).
Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
  J Med Chem, 53, 1563-1578.  
20890793 A.Tsujimura, H.Kiyoi, Y.Shiotsu, Y.Ishikawa, Y.Mori, H.Ishida, T.Toki, E.Ito, and T.Naoe (2010).
Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia.
  Int J Hematol, 92, 624-633.  
20095048 H.M.Zhang, X.Yu, M.J.Greig, K.S.Gajiwala, J.C.Wu, W.Diehl, E.A.Lunney, M.R.Emmett, and A.G.Marshall (2010).
Drug binding and resistance mechanism of KIT tyrosine kinase revealed by hydrogen/deuterium exchange FTICR mass spectrometry.
  Protein Sci, 19, 703-715.  
20147452 J.P.DiNitto, G.D.Deshmukh, Y.Zhang, S.L.Jacques, R.Coli, J.W.Worrall, W.Diehl, J.M.English, and J.C.Wu (2010).
Function of activation loop tyrosine phosphorylation in the mechanism of c-Kit auto-activation and its implication in sunitinib resistance.
  J Biochem, 147, 601-609.  
20361266 P.A.Cassier, and J.Y.Blay (2010).
Molecular response prediction in gastrointestinal stromal tumors.
  Target Oncol, 5, 29-37.  
20205869 S.Pati, G.U.Gurudutta, O.P.Kalra, and A.Mukhopadhyay (2010).
The structural insights of stem cell factor receptor (c-Kit) interaction with tyrosine phosphatase-2 (Shp-2): An in silico analysis.
  BMC Res Notes, 3, 14.  
20595514 Z.Orinska, N.Föger, M.Huber, J.Marschall, F.Mirghomizadeh, X.Du, M.Scheller, P.Rosenstiel, T.Goldmann, A.Bollinger, B.A.Beutler, and S.Bulfone-Paus (2010).
I787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development.
  Blood, 116, 2665-2675.  
19290926 A.M.Gilfillan, and J.Rivera (2009).
The tyrosine kinase network regulating mast cell activation.
  Immunol Rev, 228, 149-169.  
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
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
19560417 M.Red Brewer, S.H.Choi, D.Alvarado, K.Moravcevic, A.Pozzi, M.A.Lemmon, and G.Carpenter (2009).
The juxtamembrane region of the EGF receptor functions as an activation domain.
  Mol Cell, 34, 641-651.
PDB code: 3gop
19861435 N.Girard, R.Shen, T.Guo, M.F.Zakowski, A.Heguy, G.J.Riely, J.Huang, C.Lau, A.E.Lash, M.Ladanyi, A.Viale, C.R.Antonescu, W.D.Travis, V.W.Rusch, M.G.Kris, and W.Pao (2009).
Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.
  Clin Cancer Res, 15, 6790-6799.  
19165540 N.Naqvi, M.Li, E.Yahiro, R.M.Graham, and A.Husain (2009).
Insights into the characteristics of mammalian cardiomyocyte terminal differentiation shown through the study of mice with a dysfunctional c-kit.
  Pediatr Cardiol, 30, 651-658.  
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.  
19176456 T.Negri, G.M.Pavan, E.Virdis, A.Greco, M.Fermeglia, M.Sandri, S.Pricl, M.A.Pierotti, S.Pilotti, and E.Tamborini (2009).
T670X KIT mutations in gastrointestinal stromal tumors: making sense of missense.
  J Natl Cancer Inst, 101, 194-204.  
19248173 V.Di Felice, A.De Luca, M.L.Colorito, A.Montalbano, N.M.Ardizzone, F.Macaluso, A.M.Gammazza, F.Cappello, and G.Zummo (2009).
Cardiac stem cell research: an elephant in the room?
  Anat Rec (Hoboken), 292, 449-454.  
18500355 B.M.Jensen, C.Akin, and A.M.Gilfillan (2008).
Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders.
  Br J Pharmacol, 154, 1572-1582.  
18039140 C.L.Corless, and M.C.Heinrich (2008).
Molecular pathobiology of gastrointestinal stromal sarcomas.
  Annu Rev Pathol, 3, 557-586.  
19060208 H.Chen, C.F.Xu, J.Ma, A.V.Eliseenkova, W.Li, P.M.Pollock, N.Pitteloud, W.T.Miller, T.A.Neubert, and M.Mohammadi (2008).
A crystallographic snapshot of tyrosine trans-phosphorylation in action.
  Proc Natl Acad Sci U S A, 105, 19660-19665.
PDB code: 3cly
18184589 J.Eswaran, A.Bernad, J.M.Ligos, B.Guinea, J.E.Debreczeni, F.Sobott, S.A.Parker, R.Najmanovich, B.E.Turk, and S.Knapp (2008).
Structure of the human protein kinase MPSK1 reveals an atypical activation loop architecture.
  Structure, 16, 115-124.  
18214972 J.Zou, Y.D.Wang, F.X.Ma, M.L.Xiang, B.Shi, Y.Q.Wei, and S.Y.Yang (2008).
Detailed conformational dynamics of juxtamembrane region and activation loop in c-Kit kinase activation process.
  Proteins, 72, 323-332.  
17949810 T.Kajiguchi, S.Lee, M.J.Lee, J.B.Trepel, and L.Neckers (2008).
KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia.
  Leuk Res, 32, 761-770.  
18451558 Y.Mori, T.Hirokawa, K.Aoki, H.Satomi, S.Takeda, M.Aburada, and K.Miyamoto (2008).
Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.
  Chem Pharm Bull (Tokyo), 56, 682-687.  
17660253 C.N.Cronin, K.B.Lim, and J.Rogers (2007).
Production of selenomethionyl-derivatized proteins in baculovirus-infected insect cells.
  Protein Sci, 16, 2023-2029.  
17325667 D.Mahadevan, L.Cooke, C.Riley, R.Swart, B.Simons, K.Della Croce, L.Wisner, M.Iorio, K.Shakalya, H.Garewal, R.Nagle, and D.Bearss (2007).
A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors.
  Oncogene, 26, 3909-3919.  
17588355 E.A.Choi, and B.W.Feig (2007).
Surgical resection in metastatic gastrointestinal stromal tumors.
  Curr Oncol Rep, 9, 303-308.  
17803937 H.Chen, J.Ma, W.Li, A.V.Eliseenkova, C.Xu, T.A.Neubert, W.T.Miller, and M.Mohammadi (2007).
A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.
  Mol Cell, 27, 717-730.
PDB codes: 2psq 2pvf 2pvy 2pwl 2py3 2pz5 2pzp 2pzr 2q0b
17517053 J.Pan, A.Quintás-Cardama, T.Manshouri, J.Cortes, H.Kantarjian, and S.Verstovsek (2007).
Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406.
  Cancer Sci, 98, 1223-1225.  
17612398 L.Magnol, M.C.Chevallier, V.Nalesso, S.Retif, H.Fuchs, M.Klempt, P.Pereira, M.Riottot, S.Andrzejewski, B.T.Doan, J.J.Panthier, A.Puech, J.C.Beloeil, M.H.de Angelis, and Y.Hérault (2007).
KIT is required for hepatic function during mouse post-natal development.
  BMC Dev Biol, 7, 81.  
16948123 A.Quintas-Cardama, A.Aribi, J.Cortes, F.J.Giles, H.Kantarjian, and S.Verstovsek (2006).
Novel approaches in the treatment of systemic mastocytosis.
  Cancer, 107, 1429-1439.  
  16931579 C.Akin (2006).
Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology.
  J Mol Diagn, 8, 412-419.  
16751810 E.Tamborini, S.Pricl, T.Negri, M.S.Lagonigro, F.Miselli, A.Greco, A.Gronchi, P.G.Casali, M.Ferrone, M.Fermeglia, A.Carbone, M.A.Pierotti, and S.Pilotti (2006).
Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients.
  Oncogene, 25, 6140-6146.  
15625120 J.Lennartsson, T.Jelacic, D.Linnekin, and R.Shivakrupa (2005).
Normal and oncogenic forms of the receptor tyrosine kinase kit.
  Stem Cells, 23, 16-43.  
15737214 T.Murakami, N.Hosomi, N.Oiso, M.L.Giovannucci-Uzielli, R.Aquaron, M.Mizoguchi, A.Kato, M.Ishii, M.Bitner-Glindzicz, A.Barnicoat, L.Wilson, K.Tsukamoto, H.Ueda, A.J.Mancini, T.Suzuki, J.Riley, J.Miertus, M.Camargo, A.Santoro-Zea, J.Atkin, and K.Fukai (2005).
Analysis of KIT, SCF, and initial screening of SLUG in patients with piebaldism.
  J Invest Dermatol, 124, 670-672.  
15062077 G.Snell, C.Cork, R.Nordmeyer, E.Cornell, G.Meigs, D.Yegian, J.Jaklevic, J.Jin, R.C.Stevens, and T.Earnest (2004).
Automated sample mounting and alignment system for biological crystallography at a synchrotron source.
  Structure, 12, 537-545.  
14759363 J.Griffith, J.Black, C.Faerman, L.Swenson, M.Wynn, F.Lu, J.Lippke, and K.Saxena (2004).
The structural basis for autoinhibition of FLT3 by the juxtamembrane domain.
  Mol Cell, 13, 169-178.
PDB code: 1rjb
15343278 N.J.Dibb, S.M.Dilworth, and C.D.Mol (2004).
Switching on kinases: oncogenic activation of BRAF and the PDGFR family.
  Nat Rev Cancer, 4, 718-727.  
15452163 S.Carvalho, A.O.e Silva, F.Milanezi, S.Ricardo, D.Leitão, I.Amendoeira, and F.C.Schmitt (2004).
c-KIT and PDGFRA in breast phyllodes tumours: overexpression without mutations?
  J Clin Pathol, 57, 1075-1079.  
15173825 S.R.Hubbard (2004).
Juxtamembrane autoinhibition in receptor tyrosine kinases.
  Nat Rev Mol Cell Biol, 5, 464-471.  
15067126 Y.Kimura, N.Jones, M.Klüppel, M.Hirashima, K.Tachibana, J.B.Cohn, J.L.Wrana, T.Pawson, and A.Bernstein (2004).
Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages.
  Proc Natl Acad Sci U S A, 101, 6015-6020.  
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.