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

Ohren, Jeffrey F.; Huifen Chen; Pavlovsky, Alexander; Whitehead, Christopher; Zhang, Erli; Kuffa, Peter; Chunhong Yan; 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
December 2004
Nature Structural & Molecular Biology;Dec2004, Vol. 11 Issue 12, p1192
Academic Journal
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 2.4Ã…and 3.2Ã…, 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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