In addition, hairpin loop structures were found to significantly increase the efficacy of phosphodiester DNA-based TFOs in tissue culture.
Protein kinases are key enzymes in the complex regulation of cellular processes in almost all living organisms. For this reason, protein kinases represent attractive targets to stop the growth of eukaryotic pathogens such as protozoa and LEE011? fungi. However, using kinase inhibitors to fight against these organisms bears several challenges since most of them are unselective and will also affect crucial host kinases. Here we present the X-ray structure of glycogen synthase kinase 3 from the fungal plant pathogen Ustilago maydis (UmGSK3) and its inhibition by type-II kinase inhibitors.

Despite the high sequence homology between the human and the fungal variant of this vital kinase, we found substantial differences in the conformational plasticity of their active sites. Compounds that induced such conformational changes could be used to selectively inhibit the fungal kinase. This study serves as an example of how species-specific selectivity of inhibitors can be achieved by identifying and addressing the inactive state of a protein kinase. In addition to this, our study gives interesting insights into the molecular plasticity of UmGSK3 by revealing a previously unknown inactive conformation of this important kinase family.
Designing O-2-tolerant hydrogenases is a major challenge in applying [Fe-Fe]H(2)ases for H-2 production. The inhibition involves transport of oxygen through the enzyme to the H-cluster, followed by binding and subsequent deactivation of the active site.

To explore the nature of the oxygen diffusion channel for the hydrogenases from Desulfovibrio desulfuricans (Dd) and Clostridium pasteurianum (Cp), empirical molecular dynamics simulations were performed. The dynamic nature of the oxygen pathways in Dd and Cp was elucidated, and insight is provided, in part, into the experimental observation on the difference of oxygen inhibition in Dd and the hydrogenase from Clostridium acetobutylicum (Ca, assumed homologous to Cp). Further, to gain an understanding of the mechanism of oxygen inhibition of the [Fe-Fe]H(2)ase, density functional theory calculations of model compounds composed of the H-cluster and proximate amino acids are reported.

Confirmation of the experimentally based suppositions on inactivation by oxygen at the [2Fe](H) domain is provided, validating the model compounds used and oxidation state assumptions, further explaining the Brefeldin_A mode of damage. This unified approach provides insight into oxygen diffusion in the enzyme, followed by deactivation at the H-cluster.
Chemical derivatization of nucleic stains such as ethidium bromide or DAPI with tailored, photoresponsive caging groups, allows Perifosine for “on demand” spatiotemporal control of their in vivo nucleic acid binding, as well as for improving their cellular uptake.