8YP4

Structure of MAP2K1 complexed with 5Z7-oxozeaenol

8YP4 の概要

• エントリーDOI: 10.2210/pdb8yp4/pdb
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 1, (4~{S},9~{S},10~{S},12~{E})-16-methoxy-4-methyl-9,10,18-tris(oxidanyl)-3-oxabicyclo[12.4.0]octadeca-1(18),12,14,16-tetraene-2,8-dione, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: mitogen-activated protein kinase kinase 1, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82492.87

構造登録者

Yumura, S.,Kinoshita, T. (登録日: 2024-03-15, 公開日: 2025-01-22)

主引用文献

Yumura, S.,Kitagawa, D.,Moritsugu, K.,Nakayama, A.,Shinada, T.,Sawa, M.,Kinoshita, T.
Conserved gatekeeper methionine regulates the binding and access of kinase inhibitors to ATP sites of MAP2K1, 4, and 7: Clues for developing selective inhibitors.
Bioorg.Med.Chem.Lett., 112:129914-129914, 2024

PubMed Abstract: 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.

PubMed: 39111728
DOI: 10.1016/j.bmcl.2024.129914

実験手法

X-RAY DIFFRACTION (2.35 Å)