Structure of mitogen-activated protein kinase kinase 1 in the DFG-out conformation

Eukaryotic protein kinases contain an Asp-Phe-Gly (DFG) motif, the conformation of which is involved in controlling the catalytic activity, at the N-terminus of the activation segment. The motif can be switched between active-state (DFG-in) and inactive-state (DFG-out) conformations: however, the mechanism of conformational change is poorly understood, partly because there are few reports of the DFG-out conformation. Here, a novel crystal structure of nonphosphorylated human mitogen-activated protein kinase kinase 1 (MEK1; amino acids 38 – 381) complexed with ATP- γ S is reported in which MEK1 adopts the DFG-out conformation. The crystal structure revealed that the structural elements (the α C helix and HRD motif) surrounding the active site are involved in the formation/stabilization of the DFG-out conformation. The ATP- γ S molecule was bound to the canonical ATP-binding site in a different binding mode that has never been found in previously determined crystal structures of MEK1. This novel ATP- γ S binding mode provides a starting point for the design of high-affinity inhibitors of nonphosphorylated inactive MEK1 that adopts the DFG-out conformation.

Source: Acta Crystallographica Section F - November 25, 2021 Category: Biochemistry Authors: Nakae, S. Kitamura, M. Fujiwara, D. Sawa, M. Shirai, T. Fujii, I. Tada, T. Tags: MAP kinases human mitogen-activated protein kinase kinase 1 MEK1 DFG motif X-ray crystallography research communications Source Type: research