6qg4
Structure of the mitogen activated kinase kinase 7 in complex with pyrazolopyrimidine inhibitor 1h
Structural highlights
FunctionMP2K7_HUMAN Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by proinflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.[1] [2] [3] [:] Publication Abstract from PubMedPyrazolopyrimidines are well established as covalent inhibitors of protein kinases such as the epidermal growth factor receptor (EGFR) or Bruton's tyrosine kinase (BTK) and we recently described their potential in targeting MKK7. Herein, we report the structure-activity relationship of pyrazolopyrimidine-based MKK7 inhibitors and solved sever-al complex crystal structures to gain insights into their binding mode. In addition, we present two structures of apo-MKK7, exhibiting a DFG-out and an unprecedented DFG-in/Leu-in conformation. Characterization of Covalent Pyrazolopyrimidine-MKK7 Complexes and Report on a Unique DFG-in/Leu-in Conformation of the Mitogen Activated Protein Kinase Kinase 7 (MKK7).,Wolle P, Engel J, Smith S, Goebel L, Hennes E, Lategahn J, Rauh D J Med Chem. 2019 May 14. doi: 10.1021/acs.jmedchem.9b00472. PMID:31083997[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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