Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

• Published in: Nature structural & molecular biology Vol. 11; no. 12; pp. 1192 - 1197
• Main Authors: Hasemann, Charles A, Ohren, Jeffrey F, Chen, Huifen, Pavlovsky, Alexander, Whitehead, Christopher, Zhang, Erli, Kuffa, Peter, Yan, Chunhong, McConnell, Patrick, Spessard, Cindy, Banotai, Craig, Mueller, W Thomas, Delaney, Amy, Omer, Charles, Sebolt-Leopold, Judith, Dudley, David T, Leung, Iris K, Flamme, Cathlin, Warmus, Joseph, Kaufman, Michael, Barrett, Stephen, Tecle, Haile
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2004
• Subjects: Binding Sites; Cellular signal transduction; Conserved Sequence; Crystal structure; Dimerization; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kinases; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - chemistry; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - antagonists & inhibitors; MAP Kinase Kinase 2 - chemistry; MAP Kinase Kinase 2 - metabolism; Models, Molecular; Molecular Structure; Phosphorylation; Physiological aspects; Protein kinases; Protein Structure, Quaternary; Proteins; Structural Homology, Protein; Structure; United States; Ann Arbor Michigan; United States > US; Michigan
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb859

MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.