Figure 3. Inhibitors stabilize different conformations of the BTK kinase domain.

(a) Co-crystal structures of BTK linker-kinase domain (light gray cartoon) bound to Ibrutinib (PDB ID: 5P9J), GDC-0853 (PDB ID: 5VFI), CGI1746 (PDB ID: 3OCS), and CC-292 (PDB ID: 5P9L) in the inactive kinase conformation. The inhibitors are shown as pink sticks, the kinase activation loop is purple and the Y551 and W395 residues are shown as yellow spheres. The αC-helix is labeled in the first structure and the two irreversible, covalent inhibitors, Ibrutinib and CC-292, are indicated. Electron density for W395 in the BTK:CGI1746 co-crystal structure and part of the activation loop (purple dashed line) in the BTK:CC-292 co-crystal structure is missing. (b) Superposition of the BTK:Ibrutinib, GDC-0853, CGI1746, and CC-292 co-crystal structures shows no major structural variations in the kinase domains. (c) Structure of BTK linker-kinase domain (dark gray cartoon) bound to Dasatinib (PDB ID: 3K54) in the active kinase conformation. The activation loop is missing in the structure and is shown as a purple dashed line. Dasatinib is shown as pink sticks, W395 (yellow spheres) and the αC-helix are labeled. (d) Superposition of the Dasatinib- (dark gray) and Ibrutinib-bound (light gray) BTK linker-kinase co-crystal structures show the inward movement of the αC-helix and the change in W395 rotamer conformation that accompanies kinase activation (see expanded inset). The BTK:Dasatinib crystal complex was obtained by co-crystallization, whereas the other BTK drug complexes were obtained by soaking BTK crystals with the drug (Bender et al., 2017; Marcotte et al., 2010).