Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.

[1]  Matthew B. Wilson,et al.  Transformation of Myeloid Leukemia Cells to Cytokine Independence by Bcr-Abl Is Suppressed by Kinase-defective Hck* , 2000, The Journal of Biological Chemistry.

[2]  A. Kazlauskas,et al.  c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. , 1999, Genes & development.

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

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

[5]  C. Sawyers.  Chronic myeloid leukemia. , 1999, The New England journal of medicine.

[6]  E. Goldsmith,et al.  Structural basis of inhibitor selectivity in MAP kinases. , 1998, Structure.

[7]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[8]  S. Hubbard,et al.  Autoregulatory Mechanisms in Protein-tyrosine Kinases* , 1998, The Journal of Biological Chemistry.

[9]  G. Superti-Furga,et al.  An intramolecular SH3-domain interaction regulates c-Abl activity , 1998, Nature Genetics.

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

[11]  G. Bemis,et al.  The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase. , 1997, Chemistry & biology.

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

[13]  Jürg Zimmermann,et al.  Potent and selective inhibitors of the Abl-kinase: phenylamino-pyrimidine (PAP) derivatives , 1997 .

[14]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

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

[16]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

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

[18]  D. Kassel,et al.  Characterization of pp60c-src tyrosine kinase activities using a continuous assay: autoactivation of the enzyme is an intermolecular autophosphorylation process. , 1995, Biochemistry.

[19]  Charis Eng,et al.  Catalytic specificity of protein-tyrosine kinases is critical for selective signalling , 1995, Nature.

[20]  J M Thornton,et al.  LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. , 1995, Protein engineering.

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

[22]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[23]  D. Baltimore,et al.  N‐terminal mutations activate the leukemogenic potential of the myristoylated form of c‐abl. , 1989, The EMBO journal.

[24]  J. Wang,et al.  Deletion of an N‐terminal regulatory domain of the c‐abl tyrosine kinase activates its oncogenic potential. , 1989, The EMBO journal.