Identification of biological targets for argon

CERVOXYNational audienc

A method for the identification of potentially bioactive argon binding sites in protein families

CERVOXYInternational audienceArgon belongs to the group of chemically inert noble gases, which display a remarkable spectrum of clinically useful biological properties. In an attempt to better understand noble gases, notably argon's mechanism of action, we mined a massive noble gas modelling database which lists all possible noble gas binding sites in the proteins from the Protein Data Bank. We developed a method of analysis to identify amongst all predicted noble gas binding sites, the potentially relevant ones within protein families which are likely to be modulated by Ar. Our method consists in determining within structurally aligned proteins, the conserved binding sites whose shape, localization, hydrophobicity and binding energies are to be further examined. This method was applied to the analysis of two protein families where crystallographic noble gas binding sites have been experimentally determined. Our findings indicate that amongst the most conserved binding sites, either the most hydrophobic one and/or the site which has the best binding energy correspond to the crystallographic noble gas binding sites with the best occupancies, therefore the best affinity for the gas. This method will allow us to predict relevant noble gas binding sites that have potential pharmacological interest and thus potential Ar targets that will be prioritized for further studies including in vitro validation

Identification of biological targets for argon

CERVOXYInternational audienc

Identification of biological targets for argon

CERVOXYInternational audienc

Identification of biological targets for argon

CERVOXYNational audienc

Identification of biological targets for argon

CERVOXYNational audienc

A Novel Nuclear Export Signal and a REF Interaction Domain Both Promote mRNA Export by the Epstein-Barr Virus EB2 Protein

International audienceA striking characteristic of mRNA export factors is that they shuttle continuously between the cytoplasm and the nucleus. This shuttling is mediated by specific factors interacting with peptide motifs called nuclear export signals (NES) and nuclear localization signals. We have identified a novel CRM-1-independent transfer-able NES and two nuclear localization signals in the Epstein-Barr virus mRNA export factor EB2 (also called BMLF1, Mta, or SM) localized at the N terminus of the protein between amino acids 61 and 146. We have also found that a previously described double NES (amino acids 213-236) does not mediate the nuclear shuttling of EB2, but is an interaction domain with the cellular export factor REF in vitro. This newly characterized REF interaction domain is essential for EB2-mediated mRNA export. Accordingly, in vivo, EB2 is found in complexes containing REF as well as the cellular factor TAP. However , these interactions are RNase-sensitive, suggesting that the RNA is an essential component of these complexes

A Massive In Silico Study of Noble Gas Binding to the Structural Proteome

CERVOXY COLLInternational audienceNoble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas–protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas–protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop “atomic drugs” that can fully exploit their considerable and relatively unexplored potential in medicine