Structure of mitogen-activated protein kinase kinase 1 in the DFG-out conformation.
Nakae, S., Kitamura, M., Fujiwara, D., Sawa, M., Shirai, T., Fujii, I., Tada, T.(2021) Acta Crystallogr F Struct Biol Commun 77: 459-464
- PubMed: 34866601 
- DOI: https://doi.org/10.1107/S2053230X21011687
- Primary Citation of Related Structures:  
3W8Q - PubMed Abstract: 
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-γS is reported in which MEK1 adopts the DFG-out conformation. The crystal structure revealed that the structural elements (the αC helix and HRD motif) surrounding the active site are involved in the formation/stabilization of the DFG-out conformation. The ATP-γS 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-γS binding mode provides a starting point for the design of high-affinity inhibitors of nonphosphorylated inactive MEK1 that adopts the DFG-out conformation.
Organizational Affiliation: 
Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.