Structural biology of protein tyrosine kinases

Abstract.Our current understanding of the structure, mechanism of action and modes of regulation of the protein tyrosine kinase family owes a great deal to structural biology. Structures are now available for more than 20 different tyrosine kinase domains, many of these in multiple conformational states. They form the basis for the design of experiments to further investigate the role of different structural elements in the normal function and regulation of the protein and in the pathogenesis of many human diseases. Once thought to be too similar to be specifically inhibited by a small molecule, structural differences between kinases allow the design of compounds which inhibit only an acceptable few. This review gives a general overview of protein tyrosine kinase structural biology, including a discussion of the strengths and limitations of the investigative methods involved.

[1]  G. Daley,et al.  Mechanisms of Autoinhibition and STI-571/Imatinib Resistance Revealed by Mutagenesis of BCR-ABL , 2003, Cell.

[2]  W. Jahnke,et al.  Amino–acid-type selective isotope labeling of proteins expressed in Baculovirus-infected insect cells useful for NMR studies , 2003, Journal of biomolecular NMR.

[3]  John Kuriyan,et al.  Crystal structure of the Src family tyrosine kinase Hck , 1997, Nature.

[4]  J. Mestan,et al.  Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. , 2004, Biochimica et biophysica acta.

[5]  R. V. van Etten,et al.  c-Abl Has High Intrinsic Tyrosine Kinase Activity That Is Stimulated by Mutation of the Src Homology 3 Domain and by Autophosphorylation at Two Distinct Regulatory Tyrosines* , 2000, The Journal of Biological Chemistry.

[6]  S. Hubbard,et al.  Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation. , 2002, Structure.

[7]  S. Hubbard.  Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog , 1997, The EMBO journal.

[8]  D. Cowburn,et al.  Direct determination of changes of interdomain orientation on ligation: use of the orientational dependence of 15N NMR relaxation in Abl SH(32). , 1999, Biochemistry.

[9]  M. Karplus,et al.  Molecular dynamics and protein function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  X. Niu,et al.  Deletion of the Carboxyl Terminus of Tie2 Enhances Kinase Activity, Signaling, and Function , 2002, The Journal of Biological Chemistry.

[11]  M. Congreve,et al.  Fragment-based lead discovery , 2004, Nature Reviews Drug Discovery.

[12]  S. Hubbard,et al.  Protein tyrosine kinase structure and function. , 2000, Annual review of biochemistry.

[13]  J. Zheng,et al.  Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. , 1991, Science.

[14]  A. Weiss,et al.  Intramolecular Regulatory Switch in ZAP-70: Analogy with Receptor Tyrosine Kinases , 2005, Molecular and Cellular Biology.

[15]  Joseph Schlessinger,et al.  Structure of the FGF Receptor Tyrosine Kinase Domain Reveals a Novel Autoinhibitory Mechanism , 1996, Cell.

[16]  D. Robinson,et al.  The protein tyrosine kinase family of the human genome , 2000, Oncogene.

[17]  K Wüthrich,et al.  NMR - this other method for protein and nucleic acid structure determination. , 1995, Acta crystallographica. Section D, Biological crystallography.

[18]  A. Weiss,et al.  The Syk family of protein tyrosine kinases in T‐cell activation and development , 1998, Immunological reviews.

[19]  Xiaofeng Lin,et al.  Functions of the Activation Loop in Csk Protein-tyrosine Kinase* , 2003, Journal of Biological Chemistry.

[20]  A. Pautsch,et al.  Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation. , 2001, Structure.

[21]  G. Superti-Furga,et al.  Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase , 2003, Cell.

[22]  W. Miller,et al.  Engineering the Substrate Specificity of the Abl Tyrosine Kinase* , 1999, The Journal of Biological Chemistry.

[23]  S. Hubbard,et al.  Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. , 2005, Molecular cell.

[24]  Oliver Hantschel,et al.  Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. , 2006, Molecular cell.

[25]  S. Harrison,et al.  Crystal structures of c-Src reveal features of its autoinhibitory mechanism. , 1999, Molecular cell.

[26]  S. Stirdivant,et al.  Crystal Structure of the Apo, Unactivated Insulin-like Growth Factor-1 Receptor Kinase , 2002, The Journal of Biological Chemistry.

[27]  T. Pawson,et al.  Structural Basis for Autoinhibition of the EphB2 Receptor Tyrosine Kinase by the Unphosphorylated Juxtamembrane Region , 2001, Cell.

[28]  Marcel L. Verdonk,et al.  The consequences of translational and rotational entropy lost by small molecules on binding to proteins , 2002, J. Comput. Aided Mol. Des..

[29]  A M Hassell,et al.  Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. , 2000, Structure.

[30]  Oliver Zerbe.  BioNMR in drug research , 2003 .

[31]  Purification and characterization of recombinant human p50csk protein-tyrosine kinase from an Escherichia coli expression system overproducing the bacterial chaperones GroES and GroEL. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Kuriyan,et al.  Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. , 1999, Molecular cell.

[33]  Claude Preudhomme,et al.  Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. , 2002, Blood.

[34]  P. Cole,et al.  Molecular determinants for Csk-catalyzed tyrosine phosphorylation of the Src tail. , 2001, Biochemistry.

[35]  F. Lu,et al.  The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. , 2004, Molecular cell.

[36]  E. Chien,et al.  Structure of a c-Kit Product Complex Reveals the Basis for Kinase Transactivation* , 2003, Journal of Biological Chemistry.

[37]  S. Hubbard,et al.  Mechanism-based design of a protein kinase inhibitor , 2001, Nature Structural Biology.

[38]  Sheraz Yaqub,et al.  Activation of C-terminal Src kinase (Csk) by phosphorylation at serine-364 depends on the Csk-Src homology 3 domain. , 2003, The Biochemical journal.

[39]  Giulio Superti-Furga,et al.  Dynamic Coupling between the SH2 and SH3 Domains of c-Src and Hck Underlies Their Inactivation by C-Terminal Tyrosine Phosphorylation , 2001, Cell.

[40]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[41]  P. Caspers,et al.  Overproduction of bacterial chaperones improves the solubility of recombinant protein tyrosine kinases in Escherichia coli. , 1994, Cellular and molecular biology.

[42]  A. M. Stanley,et al.  Structure of the extracellular region of HER 2 alone and in complex with the Herceptin Fab , 2022 .

[43]  Michael J. Eck,et al.  Three-dimensional structure of the tyrosine kinase c-Src , 1997, Nature.

[44]  S. Knapp,et al.  Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Christian Wiesmann,et al.  Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor , 1999, Nature.

[46]  P. Furet,et al.  Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. , 1999, Pharmacology & therapeutics.

[47]  J. Schlessinger,et al.  Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. , 2000, Molecular cell.

[48]  J. Griffin,et al.  The roles of FLT3 in hematopoiesis and leukemia. , 2002, Blood.

[49]  G. Poste,et al.  A truncated v-abl-derived tyrosine-specific tyrosine kinase expressed in Escherichia coli. , 1989, Biochemical Journal.

[50]  J. Kuriyan,et al.  Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. , 2002, Cancer cell.

[51]  Hiroto Yamaguchi,et al.  Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation , 1996, Nature.

[52]  P. Comoglio,et al.  Pathway specificity for Met signalling , 2001, Nature Cell Biology.

[53]  L. Kay,et al.  New developments in isotope labeling strategies for protein solution NMR spectroscopy. , 2000, Current opinion in structural biology.

[54]  D. Fabbro,et al.  Imatinib: a selective tyrosine kinase inhibitor. , 2002, European journal of cancer.

[55]  Xiaoling Xie,et al.  Application of NMR screening in drug discovery. , 2003, Current topics in medicinal chemistry.

[56]  M. Cobb,et al.  Efficient expression in insect cells of a soluble, active human insulin receptor protein-tyrosine kinase domain by use of a baculovirus vector , 1988, Journal of virology.

[57]  D Cowburn,et al.  Novel mechanism of regulation of the non-receptor protein tyrosine kinase Csk: insights from NMR mapping studies and site-directed mutagenesis. , 2001, Journal of molecular biology.

[58]  J. Mestan,et al.  AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL , 2006, British Journal of Cancer.

[59]  Victoria A. Feher,et al.  Millisecond-timescale motions contribute to the function of the bacterial response regulator protein Spo0F , 1999, Nature.

[60]  D. Kern,et al.  The role of dynamics in allosteric regulation. , 2003, Current opinion in structural biology.

[61]  John Kuriyan,et al.  Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). , 2001, Cancer research.

[62]  G. Superti-Furga,et al.  The 2.35 A crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions. , 1997, Journal of molecular biology.

[63]  C D Kroenke,et al.  Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. , 2001, Methods in enzymology.

[64]  Osamu Miyashita,et al.  Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation. , 2005, Journal of Molecular Biology.

[65]  C. Sawyers,et al.  Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[66]  S. Hubbard,et al.  Crystal structure of the tyrosine kinase domain of the human insulin receptor , 1994, Nature.

[67]  M. Stone,et al.  NMR relaxation studies of the role of conformational entropy in protein stability and ligand binding. , 2001, Accounts of chemical research.

[68]  Andrew R. Leach,et al.  Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery , 2001, J. Chem. Inf. Comput. Sci..

[69]  P. Cole,et al.  Domain interactions in protein tyrosine kinase Csk. , 1999 .

[70]  I. Maruyama,et al.  Activation of preformed EGF receptor dimers by ligand-induced rotation of the transmembrane domain. , 2001, Journal of molecular biology.

[71]  D. A. Bosco,et al.  Enzyme Dynamics During Catalysis , 2002, Science.

[72]  D. Fabbro,et al.  The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. , 2005, Structure.

[73]  W. Fantl,et al.  Signalling by receptor tyrosine kinases. , 1993, Annual review of biochemistry.

[74]  G. Superti-Furga,et al.  Autoinhibition of c-Abl , 2002, Cell.

[75]  Thomas Peters,et al.  NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. , 2003, Angewandte Chemie.

[76]  Y. Takayama,et al.  Transmembrane Phosphoprotein Cbp Positively Regulates the Activity of the Carboxyl-terminal Src Kinase, Csk* , 2000, The Journal of Biological Chemistry.

[77]  L. Notarangelo,et al.  Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains , 2000, Molecular and Cellular Biology.

[78]  G. Sun,et al.  Affinity purification of Csk protein tyrosine kinase based on its catalytic requirement for divalent metal cations. , 2001, Protein expression and purification.

[79]  David F. Burke,et al.  Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin , 2000, Nature.

[80]  Virgil L. Woods,et al.  Phosphorylation driven motions in the COOH-terminal Src kinase, CSK, revealed through enhanced hydrogen-deuterium exchange and mass spectrometry (DXMS). , 2002, Journal of molecular biology.

[81]  R. Larson,et al.  Quality of life in patients with newly diagnosed chronic phase chronic myeloid leukemia on imatinib versus interferon alfa plus low-dose cytarabine: results from the IRIS Study. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  P. Seeburg,et al.  Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. , 2000, Science.

[83]  S. Itoh,et al.  Evidence of autophosphorylation in Txk: Y91 is an autophosphorylation site. , 2002, Biological & pharmaceutical bulletin.

[84]  Claudio Dalvit,et al.  NMR screening techniques in drug discovery and drug design , 2002 .

[85]  S. Teague.  Implications of protein flexibility for drug discovery , 2003, Nature Reviews Drug Discovery.

[86]  Jae-Hoon Kim,et al.  Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains , 2002, Cell.

[87]  M. Shibuya,et al.  A highly conserved tyrosine residue at codon 845 within the kinase domain is not required for the transforming activity of human epidermal growth factor receptor. , 1992, Biochemical and biophysical research communications.

[88]  Jeffrey W. Peng,et al.  [20] Investigation of protein motions via relaxation measurements , 1994 .

[89]  Christopher A. Lepre,et al.  Strategies for NMR Screening and Library Design , 2003 .

[90]  S. Hubbard,et al.  Structural and Biochemical Evidence for an Autoinhibitory Role for Tyrosine 984 in the Juxtamembrane Region of the Insulin Receptor* , 2003, Journal of Biological Chemistry.

[91]  M. Banfield,et al.  Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. , 2001, Structure.

[92]  D E Wemmer,et al.  Two-state allosteric behavior in a single-domain signaling protein. , 2001, Science.

[93]  Shaun K Olsen,et al.  Structural basis for fibroblast growth factor receptor activation. , 2005, Cytokine & growth factor reviews.

[94]  L. Johnson,et al.  Active and Inactive Protein Kinases: Structural Basis for Regulation , 1996, Cell.

[95]  K. Shokat,et al.  Mutant tyrosine kinases with unnatural nucleotide specificity retain the structure and phospho-acceptor specificity of the wild-type enzyme. , 2002, Chemistry & biology.

[96]  S. Hubbard,et al.  Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. , 1997, Science.

[97]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[98]  J. Mestan,et al.  In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. , 2005, Cancer research.

[99]  N. Rahimi,et al.  The Presence of a Single Tyrosine Residue at the Carboxyl Domain of Vascular Endothelial Growth Factor Receptor-2/FLK-1 Regulates Its Autophosphorylation and Activation of Signaling Molecules* , 2002, The Journal of Biological Chemistry.

[100]  W. Jahnke,et al.  Protein NMR in biomedical research , 2004, Cellular and Molecular Life Sciences CMLS.

[101]  T. Pawson,et al.  Zap 70 Tyrosine 315 Mediated by Lck-Dependent Phosphorylation the Zap 70 Protein Tyrosine Kinase Is T Cell Activation-Induced CrkII Binding to and Noah , 2005 .

[102]  Hyun-soo Cho,et al.  EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. , 2003, Molecular cell.

[103]  B. Mroczkowski,et al.  Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis. , 1999, Structure.

[104]  K. M. Popov,et al.  Structure of Pyruvate Dehydrogenase Kinase , 2001, The Journal of Biological Chemistry.

[105]  Benoît Roux,et al.  The N-terminal end of the catalytic domain of SRC kinase Hck is a conformational switch implicated in long-range allosteric regulation. , 2005, Structure.

[106]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[107]  Nathan E Hall,et al.  CR1/CR2 Interactions Modulate the Functions of the Cell Surface Epidermal Growth Factor Receptor* , 2004, Journal of Biological Chemistry.

[108]  S. Wodak,et al.  Assessment of CAPRI predictions in rounds 3–5 shows progress in docking procedures , 2005, Proteins.

[109]  J. Mestan,et al.  Allosteric inhibitors of Bcr-abl–dependent cell proliferation , 2006, Nature chemical biology.

[110]  K Gubernator,et al.  Design and synthesis of potent and highly selective thrombin inhibitors. , 1994, Journal of medicinal chemistry.

[111]  G. Superti-Furga,et al.  A Myristoyl/Phosphotyrosine Switch Regulates c-Abl , 2003, Cell.

[112]  J. Kuriyan,et al.  The Conformational Plasticity of Protein Kinases , 2002, Cell.

[113]  H. Duewel,et al.  Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation , 2003, Molecular and Cellular Biology.

[114]  L. Toledo,et al.  Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. , 2000, Structure.

[115]  P. Löw,et al.  Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases. , 2003, Biochimica et biophysica acta.

[116]  Michael Kofler,et al.  The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. , 2003, Molecular cell.

[117]  Mauno Vihinen,et al.  Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. , 2003, Molecular biology of the cell.

[118]  Xuliang Jiang,et al.  Structure of the active core of human stem cell factor and analysis of binding to its receptor Kit , 2000, The EMBO journal.

[119]  M. Eck,et al.  SAP couples Fyn to SLAM immune receptors , 2003, Nature Cell Biology.

[120]  Anna Westlund,et al.  Conformation of full‐length Bruton tyrosine kinase (Btk) from synchrotron X‐ray solution scattering , 2003, The EMBO journal.

[121]  C. Ward,et al.  Structural relationships between the insulin receptor and epidermal growth factor receptor families and other proteins. , 2004, Current opinion in drug discovery & development.

[122]  John Kuriyan,et al.  Intramolecular Regulatory Interactions in the Src Family Kinase Hck Probed by Mutagenesis of a Conserved Tryptophan Residue* , 1998, The Journal of Biological Chemistry.

[123]  D. Barford,et al.  Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. , 2000, Molecular cell.

[124]  Satoru Takeuchi,et al.  Structure of the Carboxyl-terminal Src Kinase, Csk* , 2002, The Journal of Biological Chemistry.

[125]  Ajay,et al.  The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. , 1999, Chemistry & biology.

[126]  Joseph Schlessinger,et al.  Crystal Structures of Two FGF-FGFR Complexes Reveal the Determinants of Ligand-Receptor Specificity , 2000, Cell.

[127]  W. Hendrickson,et al.  Structural interactions of fibroblast growth factor receptor with its ligands. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[128]  S. Blacklow,et al.  A Zinc Clasp Structure Tethers Lck to T Cell Coreceptors CD4 and CD8 , 2003, Science.

[129]  M. Resh,et al.  Myristylation and palmitylation of Src family members: The fats of the matter , 1994, Cell.

[130]  S. Courtneidge,et al.  Src family protein tyrosine kinases and cellular signal transduction pathways. , 1995, Current opinion in cell biology.

[131]  W. Miller,et al.  Purification of recombinant pp60v-src protein tyrosine kinase and phosphorylation of peptides with different secondary structure preference. , 1989, Biochemistry.

[132]  Claudio N. Cavasotto,et al.  Protein flexibility in ligand docking and virtual screening to protein kinases. , 2004, Journal of molecular biology.

[133]  Frank Alber,et al.  A structural perspective on protein-protein interactions. , 2004, Current opinion in structural biology.

[134]  K. Bhalla,et al.  Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. , 2006, The New England journal of medicine.

[135]  C. Yip,et al.  Quaternary structure of the insulin-insulin receptor complex. , 1999, Science.

[136]  Radha Akella,et al.  Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. , 2002, Molecular cell.

[137]  P. Workman,et al.  Design and development of signal transduction inhibitors for cancer treatment: Experience and challenges with kinase targets , 2006 .

[138]  D J Rawlings,et al.  Regulation of Btk function by a major autophosphorylation site within the SH3 domain. , 1996, Immunity.

[139]  Edouard C. Nice,et al.  Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor α , 2002, Cell.

[140]  S. Hubbard,et al.  Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain , 1998, The EMBO journal.

[141]  P. Fischer,et al.  Protein structures in virtual screening: a case study with CDK2. , 2006, Journal of medicinal chemistry.

[142]  A M Gronenborn,et al.  NMR structure determination of proteins and protein complexes larger than 20 kDa. , 1998, Current opinion in chemical biology.

[143]  Olof Larsson,et al.  Three-dimensional imaging of in situ specimens with low-dose electron tomography to analyze protein conformation. , 2004, Assay and drug development technologies.

[144]  H. Jhoti,et al.  The Discovery of Novel Protein Kinase Inhibitors by Using Fragment‐Based High‐Throughput X‐ray Crystallography , 2005, Chembiochem : a European journal of chemical biology.

[145]  Johan Schultz,et al.  Site-selective screening by NMR spectroscopy with labeled amino acid pairs. , 2002, Journal of the American Chemical Society.

[146]  M. Sliwkowski,et al.  Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor* , 2002, The Journal of Biological Chemistry.

[147]  L. Johnson,et al.  Protein Kinase Inhibitors: Insights into Drug Design from Structure , 2004, Science.

[148]  J. Shaffer,et al.  Nucleotide release and associated conformational changes regulate function in the COOH-terminal Src kinase, Csk. , 2001, Biochemistry.

[149]  Avijit Chakrabartty,et al.  Autoinhibition of the Kit Receptor Tyrosine Kinase by the Cytosolic Juxtamembrane Region , 2003, Molecular and Cellular Biology.

[150]  P. Marynen,et al.  Resistance to tyrosine kinase inhibitors: calling on extra forces. , 2005, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[151]  S. Hubbard,et al.  Expression, Characterization, and Crystallization of the Catalytic Core of the Human Insulin Receptor Protein-tyrosine Kinase Domain (*) , 1995, The Journal of Biological Chemistry.

[152]  T. Arakawa,et al.  Changes in protein conformation and dynamics upon complex formation of brain-derived neurotrophic factor and its receptor: investigation by isotope-edited Fourier transform IR spectroscopy. , 2002, Biopolymers.

[153]  Hyun-soo Cho,et al.  Structure of the Extracellular Region of HER3 Reveals an Interdomain Tether , 2002, Science.

[154]  Stevan R. Hubbard,et al.  Structure and autoregulation of the insulin-like growth factor 1 receptor kinase , 2001, Nature Structural Biology.

[155]  T. Haystead,et al.  Gamma-phosphate-linked ATP-sepharose for the affinity purification of protein kinases. Rapid purification to homogeneity of skeletal muscle mitogen-activated protein kinase kinase. , 1993, European journal of biochemistry.

[156]  K. Wilson,et al.  Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[157]  Ulf Bömer,et al.  High‐Throughput Screening for Kinase Inhibitors , 2005, Chembiochem : a European journal of chemical biology.

[158]  R. Kerbel,et al.  A Unique Autophosphorylation Site on Tie2/Tek Mediates Dok-R Phosphotyrosine Binding Domain Binding and Function , 2003, Molecular and Cellular Biology.

[159]  T. Smithgall,et al.  SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo , 2002, Nature Structural Biology.

[160]  M. Hayman,et al.  The C Terminus of RON Tyrosine Kinase Plays an Autoinhibitory Role* , 2005, Journal of Biological Chemistry.

[161]  J. Mestan,et al.  Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. , 2004, Mini reviews in medicinal chemistry.

[162]  M. Eck,et al.  Crystal Structure of the FERM Domain of Focal Adhesion Kinase* , 2006, Journal of Biological Chemistry.

[163]  Bhabatosh Chaudhuri,et al.  Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. , 2002, Pharmacology & therapeutics.

[164]  S. Hubbard,et al.  Crystallographic and Solution Studies of an Activation Loop Mutant of the Insulin Receptor Tyrosine Kinase , 2001, The Journal of Biological Chemistry.

[165]  M. Lamers,et al.  Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. , 1999, Journal of molecular biology.

[166]  Martin J. Stoermer,et al.  Current status of virtual screening as analysed by target class. , 2006, Medicinal chemistry (Shariqah (United Arab Emirates)).

[167]  Doris Hafenbradl,et al.  Signal transduction therapy with rationally designed kinase inhibitors , 2006 .

[168]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[169]  F. Uckun,et al.  Crystal Structure of Bruton's Tyrosine Kinase Domain Suggests a Novel Pathway for Activation and Provides Insights into the Molecular Basis of X-linked Agammaglobulinemia* , 2001, The Journal of Biological Chemistry.

[170]  Morgan Huse,et al.  Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12 , 1999, Cell.

[171]  P. Hajduk,et al.  Discovering High-Affinity Ligands for Proteins: SAR by NMR , 1996, Science.

[172]  Duncan E McRee,et al.  Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography. , 2002, Structure.