4RVT

MAP4K4 in complex with a pyridin-2(1H)-one derivative

Summary for 4RVT

• Entry DOI: 10.2210/pdb4rvt/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 4, 3-hexanoyl-4-hydroxy-5-(4-hydroxyphenyl)pyridin-2(1H)-one, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: pyridin-2(1h)-one ligand, type i, dfg-in, serine/threonine kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : O95819
• Total number of polymer chains: 2
• Total formula weight: 75568.34

Authors

Richters, A.,Becker, C.,Kleine, S.,Rauh, D. (deposition date: 2014-11-27, release date: 2015-05-27, Last modification date: 2023-09-20)

Primary citation

Schroder, P.,Forster, T.,Kleine, S.,Becker, C.,Richters, A.,Ziegler, S.,Rauh, D.,Kumar, K.,Waldmann, H.
Neuritogenic Militarinone-Inspired 4-Hydroxypyridones Target the Stress Pathway Kinase MAP4K4.
Angew.Chem.Int.Ed.Engl., 54:12398-12403, 2015

PubMed Abstract: Progressive loss and impaired restoration of neuronal activity are hallmarks of neurological diseases, and new small molecules with neurotrophic activity are in high demand. The militarinone alkaloids and structurally simplified analogues with 4-hydroxy-2-pyridone core structure induce pronounced neurite outgrowth, but their protein target has not been identified. Reported herein is the synthesis of a militarinone-inspired 4-hydroxy-2-pyridone collection, its investigation for enhancement of neurite outgrowth, and the discovery of the stress pathway kinase MAP4K4 as a target of the discovered neuritogenic pyridones. The most potent 4-hydroxy-2-pyridone is a selective ATP-competitive inhibitor of MAP4K4 but not of the other stress pathway related kinases, as proven by biochemical analysis and by a crystal structure of the inhibitor in complex with MAP4K4. The findings support the notion that MAP4K4 may be a new target for the treatment of neurodegenerative diseases.

PubMed: 25908259
DOI: 10.1002/anie.201501515

Experimental method

X-RAY DIFFRACTION (2.4 Å)