Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase
Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, Kuriyan
Cell. 2003 Mar 21;112(6):859-71.
A Myristoyl/Phosphotyrosine Switch Regulates c-Abl
Hantschel O, Nagar B, Guettler S, Kretzschmar J, Dorey K, Kuriyan J, Superti-Furga G.
Cell. 2003 Mar 21;112(6):845-57.Mini-Review on the above papers - Cell. 2003 Mar 21;112(6):737-40.
Abstract / Figures from the paper / PDB coordinates
Abstract:
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.
Illustrations from the paper. Click on the small image to get a bigger one.
PDB Coordinates
Structural Basis For The Auto-Inhibition Of C-Abl Tyrosine Kinase (PDB code 1OPJ) : Structure A
Structural Basis For The Auto-Inhibition Of C-Abl Tyrosine Kinase (PDB code 1OPL) : Structure B
Structural Basis For The Auto-Inhibition Of C-Abl Tyrosine Kinase (PDB code 1OPK) : Structure C