A crucial role of Cys218 in configuring an unprecedented auto-inhibition form of MAP2K7

• Published in: Biochemical and biophysical research communications Vol. 473; no. 2; pp. 476 - 481
• Main Authors: Sogabe, Yuri, Hashimoto, Takuma, Matsumoto, Takashi, Kirii, Yasuyuki, Sawa, Masaaki, Kinoshita, Takayoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.04.2016
• Subjects: Adenosine Triphosphate - metabolism; Auto-inhibition form; Crystallography, X-Ray; Humans; MAP Kinase Kinase 7 - chemistry; MAP Kinase Kinase 7 - genetics; MAP Kinase Kinase 7 - metabolism; MAP2K7; Models, Molecular; Point Mutation; Protein Conformation; X-ray crystal structure; X-ray crystal structure; AMPPCP; MAP2K7; Auto-inhibition form; JNK
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.03.036

Mitogen-activated protein kinase kinase 7 (MAP2K7) is an indispensable kinase of the c-Jun N-terminal kinase signal cascade and is rigorously regulated via phosphorylation. To investigate the regulatory mechanism of the inactive non-phosphorylated state of MAP2K7, the crystal structures of the wild-type and C218S mutant were solved. The wild-type apo-structure revealed an unprecedented auto-inhibition form that occluded the ATP site. This closed form was configured by the n-σ* interaction of Cys218, a non-conserved residue among the MAP2K family kinases, with Gly145 in the glycine-rich loop. The interaction was unaltered in the presence of an ATP analog, whereas the C218S mutation precluded the closed configuration. These structural insights are potentially valuable for drug discovery of highly selective MAP2K7 inhibitors. •Crystal structures of the wild type and C218S mutant of MAP2K7 were determined.•Cys218 plays a crucial role in configuring an auto-inhibition form of MAP2K7.•The conformation is mainly fixed by the n-σ* interaction involving Cys218.