1S9I
X-ray structure of the human mitogen-activated protein kinase kinase 2 (MEK2)in a complex with ligand and MgATP
Summary for 1S9I
Entry DOI | 10.2210/pdb1s9i/pdb |
Related | 1s9j |
Descriptor | Dual specificity mitogen-activated protein kinase kinase 2, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total) |
Functional Keywords | protein kinase-ligand-mgatp complex, protein-protein interactions, transferase |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 2 |
Total formula weight | 81346.29 |
Authors | Ohren, J.F.,Chen, H.,Pavlovsky, A.,Whitehead, C.,Yan, C.,McConnell, P.,Delaney, A.,Dudley, D.T.,Sebolt-Leopold, J.,Hasemann, C.A. (deposition date: 2004-02-04, release date: 2004-11-23, Last modification date: 2024-04-03) |
Primary citation | Ohren, J.F.,Chen, H.,Pavlovsky, A.,Whitehead, C.,Zhang, E.,Kuffa, P.,Yan, C.,McConnell, P.,Spessard, C.,Banotai, C.,Mueller, W.T.,Delaney, A.,Omer, C.,Sebolt-Leopold, J.,Dudley, D.T.,Leung, I.K.,Flamme, C.,Warmus, J.,Kaufman, M.,Barrett, S.,Tecle, H.,Hasemann, C.A. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat.Struct.Mol.Biol., 11:1192-1197, 2004 Cited by PubMed 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. PubMed: 15543157DOI: 10.1038/nsmb859 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (3.2 Å) |
Structure validation
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