Nature Structural & Molecular Biology
11, 1192 - 1197 (2004)
Published online: 14 November 2004; | doi:10.1038/nsmb859
There is a Corrigendum (March 2005) associated with this Article.
Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibitionJeffrey F Ohren1, 6, Huifen Chen1, 6, Alexander Pavlovsky1, Christopher Whitehead1, Erli Zhang1, Peter Kuffa1, 5, Chunhong Yan1, Patrick McConnell1, Cindy Spessard1, Craig Banotai1, W Thomas Mueller1, Amy Delaney2, Charles Omer2, 5, Judith Sebolt-Leopold2, David T Dudley2, Iris K Leung3, Cathlin Flamme4, Joseph Warmus4, Michael Kaufman4, Stephen Barrett4, Haile Tecle4
& Charles A Hasemann11
Department of Discovery Technologies, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. 2
Departments of Molecular Sciences and Technologies, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. 3
Department of Genomics and Biotechnology, Pfizer Global Research & Development, 700 Chesterfield Parkway, Chesterfield, Missouri 63017, USA. 4
Department of Chemistry, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. 5
Present addresses: Chemistry Department, University of Michigan, 930 N. University, Ann Arbor, Michigan 48109, USA (P.K.) and Department of Cancer Biology, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA (C.O.). 6
These authors contributed equally to this work.
Correspondence should be addressed to Charles A Hasemann Charles.Hasemann@Pfizer.comMEK1 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 Å and 3.2 Å, 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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