Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.
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.
Ohren
Jeffrey F
JF
Department of Discovery Technologies, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Chen
Huifen
H
Pavlovsky
Alexander
A
Whitehead
Christopher
C
Zhang
Erli
E
Kuffa
Peter
P
Yan
Chunhong
C
McConnell
Patrick
P
Spessard
Cindy
C
Banotai
Craig
C
Mueller
W Thomas
WT
Delaney
Amy
A
Omer
Charles
C
Sebolt-Leopold
Judith
J
Dudley
David T
DT
Leung
Iris K
IK
Flamme
Cathlin
C
Warmus
Joseph
J
Kaufman
Michael
M
Barrett
Stephen
S
Tecle
Haile
H
Hasemann
Charles A
CA
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
D004791:Enzyme Inhibitors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2