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3bhy
From Proteopedia
| 3bhy, resolution 1.24Å () | |||||||||
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| Sites: | and | ||||||||
| Ligands: | , | ||||||||
| Gene: | DAPK3, ZIPK (Homo sapiens) | ||||||||
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Crystal structure of human death associated protein kinase 3 (DAPK3) in complex with a beta-carboline ligand
Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-beta-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.
7,8-Dichloro-1-oxo-beta-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes., Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S, Bracher F, J Med Chem. 2012 Jan 12;55(1):403-13. Epub 2012 Jan 3. PMID:22136433
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
3bhy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S, Bracher F. 7,8-Dichloro-1-oxo-beta-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes. J Med Chem. 2012 Jan 12;55(1):403-13. Epub 2012 Jan 3. PMID:22136433 doi:10.1021/jm201286z
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Arrowsmith, C H. | Berridge, G. | Bracher, F. | Delft, F von. | Edwards, A M. | Eswaran, J. | Fedorov, O. | Filippakopoulos, P. | Huber, K. | Knapp, S. | Niesen, F. | Pike, A C.W. | Rellos, P. | Roos, A. | SGC, Structural Genomics Consortium. | Weigelt, J. | Apoptosis | Atp-binding | Chromatin regulator | Dap kinase 3 | Dap like kinase | Dapk3 | Death associated kinase | Dlk | Nucleotide-binding | Nucleus | Serine/threonine-protein kinase | Sgc | Structural genomics consortium | Transferase | Zip kinase | Zipk
