6YG2

Crystal structure of MKK7 (MAP2K7) in complex with ibrutnib, with covalent and allosteric binding modes

Summary for 6YG2

• Entry DOI: 10.2210/pdb6yg2/pdb
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 7, 1,2-ETHANEDIOL, DIMETHYL SULFOXIDE, ... (6 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: 1
• Total formula weight: 36636.71

Authors

Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-03-27, release date: 2020-08-12, Last modification date: 2024-10-23)

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 Å)