Fig. 2

Conformational changes associated with Src family kinase activation and inhibition. Left, inactive conformation of Src family kinases is associated with lack of membrane binding, lack of phosphorylation of the activation loop tyrosine, phosphorylation of the C-terminal regulatory region tyrosine; and characterized by a “closed conformation”. The closed conformation is maintained through inhibitory SH3-SH2 domain interactions with the catalytic domain (SH1), and the C-terminal regulatory phosphotyrosine interaction with the SH2 domain. These interactions prevent ligand substrate binding. Right, Active “open” conformation allows for ligand binding and autophosphorylation of the activation loop tyrosine. The balance of active/inactive conformation is regulated by Csk that promotes phosphorylation of C-terminal tyrosine; and its dephosphorylation by PTP1B/Shp1/2. Ligand binding facilitates activation but may also regulate kinase activity through restricting access (competitive inhibition) to the active catalytic domain. Examples of SRC kinase ligands/substrates are listed on the far right. Created with BioRender.com