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

Author

Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, and Hasemann CA

Subjects
Binding Sites, Conserved Sequence, Dimerization, Enzyme Inhibitors chemistry, Humans, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 2 antagonists & inhibitors, Models, Molecular, Molecular Structure, Protein Structure, Quaternary, Structural Homology, Protein, Enzyme Inhibitors pharmacology, MAP Kinase Kinase 1 chemistry, MAP Kinase Kinase 1 metabolism, MAP Kinase Kinase 2 chemistry, MAP Kinase Kinase 2 metabolism
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.

Published
2004
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