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

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

  • Nat Struct Mol Biol. 2004 Dec;11(12):1192-7. doi: 10.1038/nsmb859.
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

Affiliation

  • 1 Department of Discovery Technologies, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
PMID: 15543157 DOI: 10.1038/nsmb859
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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