Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity

We present a crystal structure of an SH2-kinase domain construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the kinase domain. We show that the presence of the SH2 domain enhances kinase activity moderately and that this effect depends on contacts in the SH2-N-lobe interface and is abrogated by specific mutations. Consistently, formation of the interface decreases slightly the association rate of imatinib with the kinase domain. That the effects are small compared to the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help disassemble the autoinhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity.

Source: BJ Signal - March 17, 2015 Category: Biochemistry Authors: S G Lorenz, P Deng, O Hantschel, G Superti-Furga, J Kuriyan Tags: BJ Signal Source Type: research