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PDBsum entry 1t46

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protein ligands links
Transferase activator PDB id
1t46
Jmol
Contents
Protein chain
297 a.a. *
Ligands
PO4 ×2
STI
Waters ×268
* Residue conservation analysis
PDB id:
1t46
Name: Transferase activator
Title: Structural basis for the autoinhibition and sti-571 inhibition of c-kit tyrosine kinase
Structure: Homo sapiens v-kit hardy-zuckerman 4 feline sarcoma viral oncogene homolog. Chain: a. Fragment: tyrosine kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: kit. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
1.60Å     R-factor:   0.190     R-free:   0.213
Authors: C.D.Mol,D.R.Dougan,T.R.Schneider,R.J.Skene,M.L.Kraus, D.N.Scheibe,G.P.Snell,H.Zou,B.C.Sang,K.P.Wilson
Key ref:
C.D.Mol et al. (2004). Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem, 279, 31655-31663. PubMed id: 15123710 DOI: 10.1074/jbc.M403319200
Date:
28-Apr-04     Release date:   15-Jun-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P10721  (KIT_HUMAN) -  Mast/stem cell growth factor receptor Kit
Seq:
Struc:
 
Seq:
Struc:
976 a.a.
297 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
+ [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.M403319200 J Biol Chem 279:31655-31663 (2004)
PubMed id: 15123710  
 
 
Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.
C.D.Mol, D.R.Dougan, T.R.Schneider, R.J.Skene, M.L.Kraus, D.N.Scheibe, G.P.Snell, H.Zou, B.C.Sang, K.P.Wilson.
 
  ABSTRACT  
 
The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.
 
  Selected figure(s)  
 
Figure 4.
FIG. 4. The structure and environment surrounding the frequently mutated residue Asp816 in the autoinhibited and activated c-Kit kinase structures. A, view of the structural environment surrounding Asp816 in the autoinhibited kinase structure. Asp816 is situated between the P-loop and a short region of 3[10] helix where the negatively charged Asp side chain can stabilize the positively charged helical dipole. B, view of the structural environment surrounding Asp816 in the activated kinase structure. Arg815 and Ile^817 form -sheet hydrogen bonding interactions with Ile^79 and Asn787 of the C-lobe to stabilize the activation loop in an extended conformation.
Figure 7.
FIG. 7. STI-571 binding and interactions with c-Kit kinase. A, chemical structure of STI-571 and F[obs] - F[calc] omit difference electron density calculated prior to building the inhibitor into the co-crystal structure, contoured at 3 (blue) and 6 (red). Key hydrogen bonds are depicted. B, stereo view of STI-571 (purple) binding to c-Kit showing key hydrogen bonds formed with the hinge residue Cys673, gatekeeper residue Thr670, and conserved residue Glu640. The polypeptide surrounding Trp557 from the virgin autoinhibited c-Kit structure is shown superimposed on the STI-571 complex structure.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 31655-31663) copyright 2004.  
  Figures were selected by the author.  

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.  
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.  
20857409 K.Krasagakis, I.Fragiadaki, M.Metaxari, S.Krüger-Krasagakis, G.N.Tzanakakis, E.N.Stathopoulos, J.Eberle, N.Tavernarakis, and A.D.Tosca (2011).
KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro.
  J Cell Physiol, 226, 1099-1109.  
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.  
21439481 N.Singla, H.Erdjument-Bromage, J.P.Himanen, T.W.Muir, and D.B.Nikolov (2011).
A semisynthetic Eph receptor tyrosine kinase provides insight into ligand-induced kinase activation.
  Chem Biol, 18, 361-371.  
20473908 P.Dileo, S.Pricl, E.Tamborini, T.Negri, S.Stacchiotti, A.Gronchi, P.Posocco, E.Laurini, P.Coco, E.Fumagalli, P.G.Casali, and S.Pilotti (2011).
Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study.
  Int J Cancer, 128, 983-990.  
21359601 P.M.Chan (2011).
Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model.
  Protein Cell, 2, 108-115.  
20569296 P.Rutkowski, M.Dębiec-Rychter, Z.Nowecki, W.Michej, M.Symonides, K.Ptaszynski, and W.Ruka (2011).
Treatment of advanced dermatofibrosarcoma protuberans with imatinib mesylate with or without surgical resection.
  J Eur Acad Dermatol Venereol, 25, 264-270.  
21262832 Y.Y.Wang, L.J.Zhao, C.F.Wu, P.Liu, L.Shi, Y.Liang, S.M.Xiong, J.Q.Mi, Z.Chen, R.Ren, and S.J.Chen (2011).
C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice.
  Proc Natl Acad Sci U S A, 108, 2450-2455.  
19865100 C.Bodemer, O.Hermine, F.Palmérini, Y.Yang, C.Grandpeix-Guyodo, P.S.Leventhal, S.Hadj-Rabia, L.Nasca, S.Georgin-Lavialle, A.Cohen-Akenine, J.M.Launay, S.Barete, F.Feger, M.Arock, B.Catteau, B.Sans, J.F.Stalder, F.Skowron, L.Thomas, G.Lorette, P.Plantin, P.Bordigoni, O.Lortholary, Y.de Prost, A.Moussy, H.Sobol, and P.Dubreuil (2010).
Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations.
  J Invest Dermatol, 130, 804-815.  
20043176 C.M.Wang, K.Huang, Y.Zhou, C.Y.Du, Y.W.Ye, H.Fu, X.Y.Zhou, and Y.Q.Shi (2010).
Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors.
  J Cancer Res Clin Oncol, 136, 1065-1071.  
20950418 E.Gregory-Bryson, E.Bartlett, M.Kiupel, S.Hayes, and V.Yuzbasiyan-Gurkan (2010).
Canine and human gastrointestinal stromal tumors display similar mutations in c-KIT exon 11.
  BMC Cancer, 10, 559.  
20718716 G.Tryggvason, B.Hilmarsdottir, G.H.Gunnarsson, J.J.Jónsson, J.G.Jónasson, and M.K.Magnússon (2010).
Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland.
  APMIS, 118, 648-656.  
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.  
19946763 J.Call, N.J.Scherzer, P.D.Josephy, and C.Walentas (2010).
Evaluation of self-reported progression and correlation of imatinib dose to survival in patients with metastatic gastrointestinal stromal tumors: an open cohort study.
  J Gastrointest Cancer, 41, 60-70.  
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.  
19950162 K.Skobridis, M.Kinigopoulou, V.Theodorou, E.Giannousi, A.Russell, R.Chauhan, R.Sala, N.Brownlow, S.Kiriakidis, J.Domin, A.G.Tzakos, and N.J.Dibb (2010).
Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors.
  ChemMedChem, 5, 130-139.  
21095574 L.M.Wodicka, P.Ciceri, M.I.Davis, J.P.Hunt, M.Floyd, S.Salerno, X.H.Hua, J.M.Ford, R.C.Armstrong, P.P.Zarrinkar, and D.K.Treiber (2010).
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
  Chem Biol, 17, 1241-1249.  
21083038 M.Arock, and P.Valent (2010).
Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives.
  Expert Rev Hematol, 3, 497-516.  
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.  
20189109 P.Ranjitkar, A.M.Brock, and D.J.Maly (2010).
Affinity reagents that target a specific inactive form of protein kinases.
  Chem Biol, 17, 195-206.  
20140688 R.Rajasekaran, and R.Sethumadhavan (2010).
Exploring the cause of drug resistance by the detrimental missense mutations in KIT receptor: computational approach.
  Amino Acids, 39, 651-660.  
  20633291 S.Caenepeel, L.Renshaw-Gegg, A.Baher, T.L.Bush, W.Baron, T.Juan, R.Manoukian, A.S.Tasker, A.Polverino, and P.E.Hughes (2010).
Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors.
  J Exp Clin Cancer Res, 29, 96.  
20939100 S.Kalkhof, S.Haehn, M.Paulsson, N.Smyth, J.Meiler, and A.Sinz (2010).
Computational modeling of laminin N-terminal domains using sparse distance constraints from disulfide bonds and chemical cross-linking.
  Proteins, 78, 3409-3427.  
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.  
20966921 W.Pao, and J.Chmielecki (2010).
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.
  Nat Rev Cancer, 10, 760-774.  
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.  
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.  
19081671 A.Torkamani, G.Verkhivker, and N.J.Schork (2009).
Cancer driver mutations in protein kinase genes.
  Cancer Lett, 281, 117-127.  
19236722 J.A.Winger, O.Hantschel, G.Superti-Furga, and J.Kuriyan (2009).
The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2).
  BMC Struct Biol, 9, 7.
PDB code: 3fw1
19404318 J.E.Cortes, M.J.Egorin, F.Guilhot, M.Molimard, and F.X.Mahon (2009).
Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia.
  Leukemia, 23, 1537-1544.  
19265199 J.Sun, M.Pedersen, and L.Rönnstrand (2009).
The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction.
  J Biol Chem, 284, 11039-11047.  
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
20041122 L.J.Yang, J.Zou, H.Z.Xie, L.L.Li, Y.Q.Wei, and S.Y.Yang (2009).
Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl.
  PLoS One, 4, e8470.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
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
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.  
19789626 P.Dubreuil, S.Letard, M.Ciufolini, L.Gros, M.Humbert, N.Castéran, L.Borge, B.Hajem, A.Lermet, W.Sippl, E.Voisset, M.Arock, C.Auclair, P.S.Leventhal, C.D.Mansfield, A.Moussy, and O.Hermine (2009).
Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.
  PLoS One, 4, e7258.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
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.  
19705869 S.T.Hsu, P.Varnai, A.Bugaut, A.P.Reszka, S.Neidle, and S.Balasubramanian (2009).
A G-rich sequence within the c-kit oncogene promoter forms a parallel G-quadruplex having asymmetric G-tetrad dynamics.
  J Am Chem Soc, 131, 13399-13409.
PDB codes: 2kj0 2kj2 2kqg 2kqh
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.  
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
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.  
19030106 D.Lietha, and M.J.Eck (2008).
Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation.
  PLoS ONE, 3, e3800.
PDB codes: 2jkk 2jkm 2jko 2jkq
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
18312355 J.Lasota, and M.Miettinen (2008).
Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours.
  Histopathology, 53, 245-266.  
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.  
18488000 L.L.Chen, J.A.Holden, H.Choi, J.Zhu, E.F.Wu, K.A.Jones, J.H.Ward, R.H.Andtbacka, R.L.Randall, C.L.Scaife, K.K.Hunt, V.G.Prieto, A.K.Raymond, W.Zhang, J.C.Trent, R.S.Benjamin, and M.L.Frazier (2008).
Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression.
  Mod Pathol, 21, 826-836.  
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
17851554 N.Brownlow, A.E.Russell, H.Saravanapavan, M.Wiesmann, J.M.Murray, P.W.Manley, and N.J.Dibb (2008).
Comparison of nilotinib and imatinib inhibition of FMS receptor signaling, macrophage production and osteoclastogenesis.
  Leukemia, 22, 649-652.  
18766971 O.Ozer, Y.D.Zhao, K.R.Ostler, C.Akin, J.Anastasi, J.W.Vardiman, and L.A.Godley (2008).
The identification and characterisation of novel KIT transcripts in aggressive mast cell malignancies and normal CD34+ cells.
  Leuk Lymphoma, 49, 1567-1577.  
18954462 T.A.Binkowski, and A.Joachimiak (2008).
Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.
  BMC Struct Biol, 8, 45.  
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.  
17483313 A.Fernández, A.Sanguino, Z.Peng, A.Crespo, E.Ozturk, X.Zhang, S.Wang, W.Bornmann, and G.Lopez-Berestein (2007).
Rational drug redesign to overcome drug resistance in cancer therapy: imatinib moving target.
  Cancer Res, 67, 4028-4033.  
18060038 A.Fernández, A.Sanguino, Z.Peng, E.Ozturk, J.Chen, A.Crespo, S.Wulf, A.Shavrin, C.Qin, J.Ma, J.Trent, Y.Lin, H.D.Han, L.S.Mangala, J.A.Bankson, J.Gelovani, A.Samarel, W.Bornmann, A.K.Sood, and G.Lopez-Berestein (2007).
An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic.
  J Clin Invest, 117, 4044-4054.  
17720713 A.K.Todd, S.M.Haider, G.N.Parkinson, and S.Neidle (2007).
Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter.
  Nucleic Acids Res, 35, 5799-5808.  
17185414 A.V.Galkin, J.S.Melnick, S.Kim, T.L.Hood, N.Li, L.Li, G.Xia, R.Steensma, G.Chopiuk, J.Jiang, Y.Wan, P.Ding, Y.Liu, F.Sun, P.G.Schultz, N.S.Gray, and M.Warmuth (2007).
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
  Proc Natl Acad Sci U S A, 104, 270-275.  
17586502 B.P.Craddock, C.Cotter, and W.T.Miller (2007).
Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region.
  FEBS Lett, 581, 3235-3240.  
17512858 B.P.Rubin, M.C.Heinrich, and C.L.Corless (2007).
Gastrointestinal stromal tumour.
  Lancet, 369, 1731-1741.  
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.  
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.  
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
18042729 K.W.Thiel, and G.Carpenter (2007).
Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation.
  Proc Natl Acad Sci U S A, 104, 19238-19243.  
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.  
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
17573850 N.C.Goddard, A.McIntyre, B.Summersgill, D.Gilbert, S.Kitazawa, and J.Shipley (2007).
KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature.
  Int J Androl, 30, 337.  
17684099 O.Hantschel, U.Rix, U.Schmidt, T.Bürckstümmer, M.Kneidinger, G.Schütze, J.Colinge, K.L.Bennett, W.Ellmeier, P.Valent, and G.Superti-Furga (2007).
The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib.
  Proc Natl Acad Sci U S A, 104, 13283-13288.  
17306972 S.R.Hubbard, and W.T.Miller (2007).
Receptor tyrosine kinases: mechanisms of activation and signaling.
  Curr Opin Cell Biol, 19, 117-123.  
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
17662946 S.Yuzawa, Y.Opatowsky, Z.Zhang, V.Mandiyan, I.Lax, and J.Schlessinger (2007).
Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor.
  Cell, 130, 323-334.
PDB codes: 2e9w 2ec8
16387853 A.Fernández, R.Scott, and R.S.Berry (2006).
Packing defects as selectivity switches for drug-based protein inhibitors.
  Proc Natl Acad Sci U S A, 103, 323-328.  
  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.  
16170366 J.R.Taylor, N.Brownlow, J.Domin, and N.J.Dibb (2006).
FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance.
  Oncogene, 25, 147-151.  
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
16917500 R.Jauch, M.K.Cho, S.Jäkel, C.Netter, K.Schreiter, B.Aicher, M.Zweckstetter, H.Jäckle, and M.C.Wahl (2006).
Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.
  EMBO J, 25, 4020-4032.
PDB codes: 2hw6 2hw7
17110166 S.Maddipati, and A.Fernández (2006).
Feature-similarity protein classifier as a ligand engineering tool.
  Biomol Eng, 23, 307-315.  
17253940 S.Sharma, G.U.Gurudutta, N.K.Satija, S.Pati, F.Afrin, P.Gupta, Y.K.Verma, V.K.Singh, and R.P.Tripathi (2006).
Stem cell c-KIT and HOXB4 genes: critical roles and mechanisms in self-renewal, proliferation, and differentiation.
  Stem Cells Dev, 15, 755-778.  
16338411 A.Fernández (2005).
Incomplete protein packing as a selectivity filter in drug design.
  Structure, 13, 1829-1836.  
16242052 C.Tarn, and A.K.Godwin (2005).
Molecular research directions in the management of gastrointestinal stromal tumors.
  Curr Treat Options Oncol, 6, 473-486.  
16313343 F.P.Ross, and S.L.Teitelbaum (2005).
alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology.
  Immunol Rev, 208, 88.  
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.  
15824741 L.L.Chen, M.Sabripour, E.F.Wu, V.G.Prieto, G.N.Fuller, and M.L.Frazier (2005).
A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors.
  Oncogene, 24, 4271-4280.  
15946589 L.L.Chen, M.Sabripour, R.H.Andtbacka, S.R.Patel, B.W.Feig, H.A.Macapinlac, H.Choi, E.F.Wu, M.L.Frazier, and R.S.Benjamin (2005).
Imatinib resistance in gastrointestinal stromal tumors.
  Curr Oncol Rep, 7, 293-299.  
15803155 S.Neidle, and D.E.Thurston (2005).
Chemical approaches to the discovery and development of cancer therapies.
  Nat Rev Cancer, 5, 285-296.  
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.  
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.