Conserved gatekeeper methionine regulates the binding and access of kinase inhibitors to ATP sites of MAP2K1, 4, and 7: Clues for developing selective inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 112; p. 129914
• Main Authors: Yumura, Seigo, Kitagawa, Daisuke, Moritsugu, Kei, Nakayama, Atsushi, Shinada, Tetsuro, Sawa, Masaaki, Kinoshita, Takayoshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2024
• Subjects: Covalent inhibitor; Crystal structure; Cysteine; MAP2Ks; Molecular dynamics; Selectivity; MAP2Ks; Molecular dynamics; Cysteine; Covalent inhibitor; Selectivity; Crystal structure
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129914

[Display omitted] •MAP2K1, 4, and 7 are potential targets for treating various diseases.•We solved the crystal structures of MAP2K1 and MAP2K4 complexed with an inhibitor.•We previously showed that this inhibitor covalently binds to MAP2K7.•These structural insights promote to develop potent and selective MAP2K inhibitors. Mitogen-activated protein kinase kinases (MAP2Ks) 1, 4, and 7 are potential targets for treating various diseases. Here, we solved the crystal structures of MAP2K1 and MAP2K4 complexed with covalent inhibitor 5Z-7-oxozeaenol (5Z7O). The elucidated structures showed that 5Z7O was non-covalently bound to the ATP binding site of MAP2K4, while it covalently attached to cysteine at the DFG-1 position of the deep ATP site of MAP2K1. In contrast, we previously showed that 5Z7O covalently binds to MAP2K7 via another cysteine on the solvent-accessible edge of the ATP site. Structural analyses and molecular dynamics calculations indicated that the configuration and mobility of conserved gatekeeper methionine located at the central ATP site regulated the binding and access of 5Z7O to the ATP site of MAP2Ks. These structural features provide clues for developing highly potent and selective inhibitors against MAP2Ks. Abbreviations: ATP, adenosine triphosphate; FDA, Food and Drug Administration; MAP2Ks, mitogen-activated protein kinase kinases; MD, molecular dynamics; NSCLC, non-small cell lung cancer; 5Z7O, 5Z-7-oxozeaenol; PDB, protein data bank; RMSD, root-mean-square deviation.