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. 2004 Dec;11(12):1192-7.
doi: 10.1038/nsmb859. Epub 2004 Nov 14.

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

Jeffrey F Ohren  1 , Huifen Chen, Alexander Pavlovsky, Christopher Whitehead, Erli Zhang, Peter Kuffa, Chunhong Yan, Patrick McConnell, Cindy Spessard, Craig Banotai, W Thomas Mueller, Amy Delaney, Charles Omer, Judith Sebolt-Leopold, David T Dudley, Iris K Leung, Cathlin Flamme, Joseph Warmus, Michael Kaufman, Stephen Barrett, Haile Tecle, Charles A Hasemann
Affiliations

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

Jeffrey F Ohren et al. Nat Struct Mol Biol. 2004 Dec.

Erratum in

  • Nat Struct Mol Biol. 2005 Mar;12(3):278

Abstract

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.

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