A crucial role of Cys218 in configuring an unprecedented auto-inhibition form of MAP2K7
| Autor: | Yuri Sogabe, Takuma Hashimoto, Yasuyuki Kirii, Takayoshi Kinoshita, Takashi Matsumoto, Masaaki Sawa |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation Mutant Biophysics MAP Kinase Kinase 7 Biology Crystallography X-Ray 01 natural sciences Biochemistry MAP2K7 03 medical and health sciences chemistry.chemical_compound Protein structure Adenosine Triphosphate Humans Point Mutation Protein kinase A Molecular Biology 010405 organic chemistry Drug discovery Kinase Cell Biology 0104 chemical sciences Cell biology 030104 developmental biology chemistry Phosphorylation Adenosine triphosphate |
| Zdroj: | Biochemical and biophysical research communications. 473(2) |
| ISSN: | 1090-2104 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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