5Z1E

MAP2K7 C218S mutant-inhibitor

Summary for 5Z1E

• Entry DOI: 10.2210/pdb5z1e/pdb
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 7, N-[3-(6-methyl-1H-indazol-3-yl)phenyl]prop-2-enamide (3 entities in total)
• Functional Keywords: protein kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37260.16

Authors

Kinoshita, T.,London, N. (deposition date: 2017-12-26, release date: 2019-01-02, Last modification date: 2023-11-22)

Primary citation

Shraga, A.,Olshvang, E.,Davidzohn, N.,Khoshkenar, P.,Germain, N.,Shurrush, K.,Carvalho, S.,Avram, L.,Albeck, S.,Unger, T.,Lefker, B.,Subramanyam, C.,Hudkins, R.L.,Mitchell, A.,Shulman, Z.,Kinoshita, T.,London, N.
Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor.
Cell Chem Biol, 26:98-108.e5, 2019

PubMed Abstract: The c-Jun NH2-terminal kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals, and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7--one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify selective MKK7 covalent inhibitors. We optimized these compounds to low-micromolar inhibitors of JNK phosphorylation in cells. The crystal structure of a lead compound bound to MKK7 demonstrated that the binding mode was correctly predicted by docking. We asserted the selectivity of our inhibitors on a proteomic level and against a panel of 76 kinases, and validated an on-target effect using knockout cell lines. Lastly, we show that the inhibitors block activation of primary mouse B cells by lipopolysaccharide. These MKK7 tool compounds will enable better investigation of JNK signaling and may serve as starting points for therapeutics.

PubMed: 30449673
DOI: 10.1016/j.chembiol.2018.10.011

Experimental method

X-RAY DIFFRACTION (2.3 Å)