1s9j

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spinqualitylabelsall models 1s9j, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP

Overview

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.

About this Structure

1S9J is a Single protein structure of sequence from Homo sapiens with MG, ATP and BBM as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

Reference

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition., 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, Hasemann CA, Nat Struct Mol Biol. 2004 Dec;11(12):1192-7. Epub 2004 Nov 14. PMID:15543157

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