Figure 4. Significance of kinase conformation for non-catalytic functions.
(A) Active conformation of the Ire1 kinase domain induces formation of a back-to-back dimer and higher order oligomers of Ire1 kinase domains that activate the adjacent RNase domain (PDB: 3FBV).
(B) Structures of mouse MLKL pseudokinase (PDB: 4M68) (left) show its activation loop in an unusual conformation, which is hypothesized to rearrange upon RIPK3-dependent phosphorylation, triggering MLKL oligomerization and necroptosis. In contrast, structures of human MLKL (PDB: 4M67) (right) show the activation loop adopting an extended conformation, possibly the conformation that results from RIPK3-dependent phosphorylation.
(C) The active conformation of the RAF kinase domain is required to transactivate a dimerization partner in a side-to-side dimer (PDB: 1UWH).
(D) Mo25 stabilizes STRADα pseudokinase in an “active” DFG-in conformation, which is necessary for LKB1 activation (PDB: 2WTK).
(E) Structures of the pseudokinase Trb1 reveal a non-canonical conformation of helix αC that creates a binding site for the C-terminal tail of Trb1 (PDB: 5CEM).
(F) In crystal structures of HER kinase asymmetric dimers (EGFR/EGFR PDB: 2GS6, HER3/EGFR PDB: 4RIW) the conformation of the allosteric activator kinase (active or Src/CDK-like inactive conformation) does not seem to matter for activation of the receiver kinase.
(G) No conformational changes in the T. gondii pseudokinase ROP5B have been implicated in regulation of the human GTPase IRGa6 (PDB: 4LV5).