Structural Basis for Autoinhibition of c-Abl Tyrosine Kinase

Journal Article · Fri Mar 21 04:00:00 EST 2003 · Cell

DOI:https://doi.org/10.1016/S0092-8674(03)00194-6· OSTI ID:881424

Nagar, Bhushan; Hantschel, Oliver; Young, Matthew A; Scheffzek, Klaus; Veach, Darren; Bornmann, William; Clarkson, Bayard; Superti-Furga, Giulio; Kuriyan, John

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 aphosphotyrosine 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.

• Research Organization: Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
• Sponsoring Organization: USDOE; National Institutes of Health Grant R01 GM45574-15; European Molecular Biology Organization and Laboratory, Human FrontierScience Program, Aventis Foundation, German National Merit Foundation,Cellzome AG, Damon Runyon Cancer Research Foundation Fellowship DRG-1553,Burroughs Wellcome Fund Career Award
• DOE Contract Number: AC02-05CH11231
• OSTI ID: 881424
• Report Number(s): LBNL--59913
• Journal Information: Cell, Journal Name: Cell Vol. 112; ISSN 0092-8674; ISSN CELLB5
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
59 BASIC BIOLOGICAL SCIENCES
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
LEUKEMIA
MODIFICATIONS
PHOSPHOTRANSFERASES
RESIDUES
TYROSINE