BIOMAT Database Logo BIOMAT Database Logo

Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. 2004

Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Syrrx, Inc., San Diego, California, 92121, USA. clifford.mol@syrrx.com

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.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000068877 Imatinib Mesylate A tyrosine kinase inhibitor and ANTINEOPLASTIC AGENT that inhibits the BCR-ABL kinase created by chromosome rearrangements in CHRONIC MYELOID LEUKEMIA and ACUTE LYMPHOBLASTIC LEUKEMIA, as well as PDG-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors. Alpha-(4-methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-tolu-p-toluidide,CGP 57148,CGP-57148,CGP57148B,Gleevec,Glivec,Imatinib,Imatinib Methanesulfonate,ST 1571,ST1571,STI 571,STI-571,STI571,CGP57148,Mesylate, Imatinib,Methanesulfonate, Imatinib

Related Publications

Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor.
August 2000, Blood,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.
September 2000, Science (New York, N.Y.),
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Structural basis for the autoinhibition of c-Abl tyrosine kinase.
March 2003, Cell,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
[Effect of STI-571, a c-kit tyrosine kinase inhibitor, in mestastasic gastrointestinal tumor].
September 2002, Medicina clinica,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
c-Abl tyrosine kinase and inhibition by the cancer drug imatinib (Gleevec/STI-571).
June 2007, The Journal of nutrition,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
STI-571: an anticancer protein-tyrosine kinase inhibitor.
October 2003, Biochemical and biophysical research communications,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region.
September 2001, Cell,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.
October 2013, Proceedings of the National Academy of Sciences of the United States of America,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Tyrosine kinase inhibitor STI-571: the new wonder drug of cancer therapy.
April 2004, Cancer biology & therapy,
Clifford D Mol, and Douglas R Dougan, and Thomas R Schneider, and Robert J Skene, and Michelle L Kraus, and Daniel N Scheibe, and Gyorgy P Snell, and Hua Zou, and Bi-Ching Sang, and Keith P Wilson
Structural basis for the autoinhibition of focal adhesion kinase.
June 2007, Cell,
Copied contents to your clipboard!