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PDBsum entry 1p4f
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protein ligands links
Transferase PDB id
1p4f

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
269 a.a. *
Ligands
86Q
Waters ×182
* Residue conservation analysis
PDB id:
1p4f
Name: Transferase
Title: Death associated protein kinase catalytic domain with bound inhibitor fragment
Structure: Death-associated protein kinase 1. Chain: a. Fragment: catalytic domain, protein kinase domain. Synonym: dap kinase 1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dapk1 or dapk. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.90Å     R-factor:   0.186     R-free:   0.233
Authors: A.V.Velentza,M.S.Wainwright,M.Zasadzki,S.Mirzoeva,J.Haiech,P.J.Focia, M.Egli,D.M.Watterson
Key ref: A.V.Velentza et al. (2003). An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury. Bioorg Med Chem Lett, 13, 3465-3470. PubMed id: 14505650 DOI: 10.1016/S0960-894X(03)00733-9
Date:
23-Apr-03     Release date:   28-Sep-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P53355  (DAPK1_HUMAN) -  Death-associated protein kinase 1 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1430 a.a.
269 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1016/S0960-894X(03)00733-9 Bioorg Med Chem Lett 13:3465-3470 (2003)
PubMed id: 14505650  
 
 
An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury.
A.V.Velentza, M.S.Wainwright, M.Zasadzki, S.Mirzoeva, A.M.Schumacher, J.Haiech, P.J.Focia, M.Egli, D.M.Watterson.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21126544 L.K.McNamara, J.S.Brunzelle, J.P.Schavocky, D.M.Watterson, and V.Grum-Tokars (2011).
Site-directed mutagenesis of the glycine-rich loop of death associated protein kinase (DAPK) identifies it as a key structure for catalytic activity.
  Biochim Biophys Acta, 1813, 1068-1073.  
20053891 B.N.Kang, A.S.Ahmad, S.Saleem, R.L.Patterson, L.Hester, S.Doré, and S.H.Snyder (2010).
Death-associated protein kinase-mediated cell death modulated by interaction with DANGER.
  J Neurosci, 30, 93-98.  
20944422 E.Y.Cho, S.J.Lee, K.W.Nam, J.Shin, K.B.Oh, K.H.Kim, and W.Mar (2010).
Amelioration of oxygen and glucose deprivation-induced neuronal death by chloroform fraction of bay leaves (Laurus nobilis).
  Biosci Biotechnol Biochem, 74, 2029-2035.  
21152427 M.Zimmermann, C.Atmanene, Q.Xu, L.Fouillen, A.Van Dorsselaer, D.Bonnet, C.Marsol, M.Hibert, S.Sanglier-Cianferani, C.Pigault, L.K.McNamara, D.M.Watterson, J.Haiech, and M.C.Kilhoffer (2010).
Homodimerization of the death-associated protein kinase catalytic domain: development of a new small molecule fluorescent reporter.
  PLoS One, 5, e14120.  
20657924 N.Gavande, G.A.Johnston, J.R.Hanrahan, and M.Chebib (2010).
Microwave-enhanced synthesis of 2,3,6-trisubstituted pyridazines: application to four-step synthesis of gabazine (SR-95531).
  Org Biomol Chem, 8, 4131-4136.  
19876042 L.K.Chico, L.J.Van Eldik, and D.M.Watterson (2009).
Targeting protein kinases in central nervous system disorders.
  Nat Rev Drug Discov, 8, 892-909.  
19237746 L.K.McNamara, D.M.Watterson, and J.S.Brunzelle (2009).
Structural insight into nucleotide recognition by human death-associated protein kinase.
  Acta Crystallogr D Biol Crystallogr, 65, 241-248.
PDB codes: 3eh9 3eha 3f5g 3f5u
17244621 C.Stevens, Y.Lin, M.Sanchez, E.Amin, E.Copson, H.White, V.Durston, D.M.Eccles, and T.Hupp (2007).
A germ line mutation in the death domain of DAPK-1 inactivates ERK-induced apoptosis.
  J Biol Chem, 282, 13791-13803.  
17487247 E.Ihara, and J.A.MacDonald (2007).
The regulation of smooth muscle contractility by zipper-interacting protein kinase.
  Can J Physiol Pharmacol, 85, 79-87.  
  17784957 L.Munoz, H.R.Ranaivo, S.M.Roy, W.Hu, J.M.Craft, L.K.McNamara, L.W.Chico, L.J.Van Eldik, and D.M.Watterson (2007).
A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model.
  J Neuroinflammation, 4, 21.  
18086004 Y.Li, and A.Grupe (2007).
Genetics of late-onset Alzheimer's disease: progress and prospect.
  Pharmacogenomics, 8, 1747-1755.  
16896543 M.Schmitt, J.X.de Araújo-Júnior, S.Oumouch, and J.J.Bourguignon (2006).
Use of 4-bromo pyridazine 3,6-dione for building 3-amino pyridazine libraries.
  Mol Divers, 10, 429-434.  
16204252 M.Shamloo, L.Soriano, T.Wieloch, K.Nikolich, R.Urfer, and D.Oksenberg (2005).
Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia.
  J Biol Chem, 280, 42290-42299.  
16009322 R.Schneider-Stock, A.Roessner, and O.Ullrich (2005).
DAP-kinase--protector or enemy in apoptotic cell death.
  Int J Biochem Cell Biol, 37, 1763-1767.  
15465624 J.M.Craft, D.M.Watterson, S.A.Frautschy, and L.J.Van Eldik (2004).
Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo.
  Neurobiol Aging, 25, 1283-1292.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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