6YG7

Crystal structure of MKK7 (MAP2K7) covalently bound with type-II inhibitor SB1-G-23

Summary for 6YG7

• Entry DOI: 10.2210/pdb6yg7/pdb
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 7, 1,2-ETHANEDIOL, ~{N}-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-[2-[[(3~{R})-1-propanoylpyrrolidin-3-yl]amino]pyrimidin-4-yl]oxy-benzamide, ... (4 entities in total)
• Functional Keywords: kinase, kinase inhibitor, mkk7, mek7, map2k7, map2k, mek, jnk signaling, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71438.85

Authors

Chaikuad, A.,Tan, L.,Wang, J.,Liang, Y.,Gray, N.S.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-03-27, release date: 2020-08-12, Last modification date: 2024-11-06)

Primary citation

Schroder, M.,Tan, L.,Wang, J.,Liang, Y.,Gray, N.S.,Knapp, S.,Chaikuad, A.
Catalytic Domain Plasticity of MKK7 Reveals Structural Mechanisms of Allosteric Activation and Diverse Targeting Opportunities.
Cell Chem Biol, 27:1285-1295.e4, 2020

PubMed Abstract: MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that affect its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small-molecule screening campaign yielded multiple scaffolds, including type II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.

PubMed: 32783966
DOI: 10.1016/j.chembiol.2020.07.014

Experimental method

X-RAY DIFFRACTION (2.2 Å)