3WIG

Human MEK1 kinase in complex with CH5126766 and MgAMP-PNP

Summary for 3WIG

• Entry DOI: 10.2210/pdb3wig/pdb
• Related: 3ORN 3OS3
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: kinase, kinase inhibitor, allosteric, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 35612.89

Authors

Lukacs, C.M.,Janson, C.,Schuck, V. (deposition date: 2013-09-12, release date: 2014-06-04, Last modification date: 2024-03-20)

Primary citation

Lito, P.,Saborowski, A.,Yue, J.,Solomon, M.,Joseph, E.,Gadal, S.,Saborowski, M.,Kastenhuber, E.,Fellmann, C.,Ohara, K.,Morikami, K.,Miura, T.,Lukacs, C.,Ishii, N.,Lowe, S.,Rosen, N.
Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors
Cancer Cell, 25:697-710, 2014

PubMed Abstract: MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF(V600E). MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.

PubMed: 24746704
DOI: 10.1016/j.ccr.2014.03.011

Experimental method

X-RAY DIFFRACTION (2.7 Å)