Structural and thermodynamic analyses of interactions between death-associated protein kinase 1 and anthraquinones

2020 ◽  
Vol 76 (5) ◽  
pp. 438-446 ◽  
Author(s):  
Takeshi Yokoyama ◽  
Peter Wijaya ◽  
Yuto Kosaka ◽  
Mineyuki Mizuguchi

Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase that regulates apoptosis and autophagy. DAPK1 is considered to be a therapeutic target for amyloid-β deposition, endometrial adenocarcinomas and acute ischemic stroke. Here, the potent inhibitory activity of the natural anthraquinone purpurin against DAPK1 phosphorylation is shown. Thermodynamic analysis revealed that while the binding affinity of purpurin is similar to that of CPR005231, which is a DAPK1 inhibitor with an imidazopyridazine moiety, the binding of purpurin was more enthalpically favorable. In addition, the inhibition potencies were correlated with the enthalpic changes but not with the binding affinities. Crystallographic analysis of the DAPK1–purpurin complex revealed that the formation of a hydrogen-bond network is likely to contribute to the favorable enthalpic changes and that stabilization of the glycine-rich loop may cause less favorable entropic changes. The present findings indicate that purpurin may be a good lead compound for the discovery of inhibitors of DAPK1, and the observation of enthalpic changes could provide important clues for drug development.

Symmetry ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 749
Author(s):  
Beata Szefler ◽  
Przemysław Czeleń

Platinum compounds are anti-cancer drugs and can bind to canonical purine bases, mainly guanine, found within double helical DNA. Platinum compounds can be transferred directly to pathologically altered sites in a specific and site-oriented manner by nanocarriers as potential nanocarriers for carboplatin. Two types of nanostructures were used as potential nanocarriers for carboplatin, the first were functionalized C60 fullerene molecules and the second were rhombellanes. The analyzed nanostructures show considerable symmetry, which affects the affinity of the studied nanocarriers and ligands. Thus symmetry of nanostructures affects the distribution of binding groups on their surface. After the docking procedure, analysis of structural properties revealed many interesting features. In all described cases, binding affinities of complexes of platinum compounds with functionalized fullerene C60 are higher compared with affinities of complexes of platinum compounds with rhombellane structures. All platinum compounds easily create complexes with functionalized fullerene C60, CID_16156307, and at the same time show the highest binding affinity. The binding affinities of lobaplatin and heptaplatin are higher compared with oxaliplatin and nedaplatin. The high value of binding affinity and equilibrium constant K is correlated with creation of strong and medium hydrogen bonds or is correlated with forming a hydrogen bond network. The performed investigations enabled finding nanocarriers for lobaplatin, heptaplatin, oxaliplatin and nedaplatin molecules.


IUCrJ ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. 131-138
Author(s):  
Takeshi Yokoyama ◽  
Ryoya Suzuki ◽  
Mineyuki Mizuguchi

Death-associated protein kinase 1 (DAPK1) is a large multidomain protein with an N-terminal serine/threonine protein kinase domain. DAPK1 is considered to be a promising molecular target for the treatment of Alzheimer's disease (AD). In the present study, the inhibitory potency of resveratrol (RSV), a dietary polyphenol found in red wine, against the catalytic activity of DAPK1 was investigated. Kinetic and fluorescent probe competitive binding analyses revealed that RSV directly inhibited the catalytic activity of DAPK1 by binding to the ATP-binding site. Crystallographic analysis of DAPK1 in complex with RSV revealed that the A-ring of RSV occupied the nucleobase-binding position. Determination of the binding mode provided a structural basis for the design of more potent DAPK1 inhibitors. In conclusion, the data here clearly show that RSV is an ATP-competitive inhibitor of DAPK1, encouraging speculation that RSV may be useful for the development of AD inhibitors.


2014 ◽  
Vol 56 (2) ◽  
pp. 129-132
Author(s):  
Takeshi YOKOYAMA ◽  
Mineyuki MIZUGUCHI ◽  
Katsuhiro KUSAKA ◽  
Ichiro TANAKA ◽  
Nobuo NIIMURA

2014 ◽  
Vol 16 (27) ◽  
pp. 14047-14058 ◽  
Author(s):  
Francisco Adasme-Carreño ◽  
Camila Muñoz-Gutierrez ◽  
Julio Caballero ◽  
Jans H. Alzate-Morales

Conformational clustering using hydrogen bond network analysis improved the MM/GBSA scoring for some protein-kinase–ligand systems used as case studies.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Matej Horvath ◽  
Olivia Petrvalska ◽  
Petr Herman ◽  
Veronika Obsilova ◽  
Tomas Obsil

AbstractDeath-associated protein kinase 2 (DAPK2) is a CaM-regulated Ser/Thr protein kinase, involved in apoptosis, autophagy, granulocyte differentiation and motility regulation, whose activity is controlled by autoinhibition, autophosphorylation, dimerization and interaction with scaffolding proteins 14-3-3. However, the structural basis of 14-3-3-mediated DAPK2 regulation remains unclear. Here, we structurally and biochemically characterize the full-length human DAPK2:14-3-3 complex by combining several biophysical techniques. The results from our X-ray crystallographic analysis revealed that Thr369 phosphorylation at the DAPK2 C terminus creates a high-affinity canonical mode III 14-3-3-binding motif, further enhanced by the diterpene glycoside Fusicoccin A. Moreover, concentration-dependent DAPK2 dimerization is disrupted by Ca2+/CaM binding and stabilized by 14-3-3 binding in solution, thereby protecting the DAPK2 inhibitory autophosphorylation site Ser318 against dephosphorylation and preventing Ca2+/CaM binding. Overall, our findings provide mechanistic insights into 14-3-3-mediated DAPK2 inhibition and highlight the potential of the DAPK2:14-3-3 complex as a target for anti‐inflammatory therapies.


Endoscopy ◽  
2005 ◽  
Vol 37 (05) ◽  
Author(s):  
GA Doherty ◽  
SM Byrne ◽  
SC Austin ◽  
GM Scully ◽  
EW Kay ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document