title: Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.
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.
authors.affiliation: Department of Discovery Technologies, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Ohren
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Alexander
authors.initials: A
authors.lastname: Pavlovsky
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitehead
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Kuffa
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.forename: Patrick
authors.initials: P
authors.lastname: McConnell
authors.forename: Cindy
authors.initials: C
authors.lastname: Spessard
authors.forename: Craig
authors.initials: C
authors.lastname: Banotai
authors.forename: W Thomas
authors.initials: WT
authors.lastname: Mueller
authors.forename: Amy
authors.initials: A
authors.lastname: Delaney
authors.forename: Charles
authors.initials: C
authors.lastname: Omer
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.forename: David T
authors.initials: DT
authors.lastname: Dudley
authors.forename: Iris K
authors.initials: IK
authors.lastname: Leung
authors.forename: Cathlin
authors.initials: C
authors.lastname: Flamme
authors.forename: Joseph
authors.initials: J
authors.lastname: Warmus
authors.forename: Michael
authors.initials: M
authors.lastname: Kaufman
authors.forename: Stephen
authors.initials: S
authors.lastname: Barrett
authors.forename: Haile
authors.initials: H
authors.lastname: Tecle
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hasemann
mesh_terms: D001665:Binding Sites; D017124:Conserved Sequence; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D020836:Protein Structure, Quaternary; D040681:Structural Homology, Protein
chemical_list: D004791:Enzyme Inhibitors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2