Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.9
Classification:TRANSFERASE
Release Date:2004-09-28
Deposition Date:2003-04-23
Revision Date:2008-04-29#2011-07-13#2017-10-11
Molecular Weight:33862.43
Macromolecule Type:Protein
Residue Count:293
Atom Site Count:2225
DOI:10.2210/pdb1p4f/pdb
Abstract:
Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development.
Resolution:1.9
Classification:TRANSFERASE
Release Date:2004-09-28
Deposition Date:2003-04-23
Revision Date:2008-04-29#2011-07-13#2017-10-11
Molecular Weight:33862.43
Macromolecule Type:Protein
Residue Count:293
Atom Site Count:2225
DOI:10.2210/pdb1p4f/pdb
Abstract:
Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development.
Date made available | 2004 |
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Publisher | RCSB-PDB |