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- Title
Structure of mitogen‐activated protein kinase kinase 1 in the DFG‐out conformation.
- Authors
Nakae, Setsu; Kitamura, Maho; Fujiwara, Daisuke; Sawa, Masaaki; Shirai, Tsuyoshi; Fujii, Ikuo; Tada, Toshiji
- 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.
- Subjects
MITOGEN-activated protein kinases; PROTEIN structure; PROTEIN kinases; CRYSTAL structure; CATALYTIC activity; MITOGENS
- Publication
Acta Crystallographica: Section F, Structural Biology Communications, 2021, Vol 77, Issue 12, p459
- ISSN
2053-230X
- Publication type
Article
- DOI
10.1107/S2053230X21011687