Structural basis for the autoinhibition of c-Abl tyrosine kinase.
c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks a phosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it. Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but with specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic activity of Abl, but not that of c-Src.
Nagar
Bhushan
B
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Hantschel
Oliver
O
Young
Matthew A
MA
Scheffzek
Klaus
K
Veach
Darren
D
Bornmann
William
W
Clarkson
Bayard
B
Superti-Furga
Giulio
G
Kuriyan
John
J
D001549:Benzamides; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D011725:Pyridines; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D001549:Benzamides; D004791:Enzyme Inhibitors; C473352:PD 166326; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; C030986:pyrimidine