Biomedical subjects

Yves Henri Sanejouand

Publications and source records attributed to Yves Henri Sanejouand.

3 recordsLinked to original sources

PubMed2006

NORMA: a tool for flexible fitting of high-resolution protein structures into low-resolution electron-microscopy-derived density maps.

This paper describes a freely available software suite that allows the modelling of large conformational changes of high-resolution three-dimensional protein structures under the constraint of a low-resolution electron-density map. Typical applications are the interpretation of electron-microscopy data using atomic scale X-ray structural models. The software package provided should enable the interested user to perform flexible fitting on new cases without encountering major technical difficulties. The NORMA software suite including three fully executable reference cases and extensive user instructions are available at http://www.elnemo.org/NORMA/.

Algorithms↗

PubMed2004

On the potential of normal-mode analysis for solving difficult molecular-replacement problems.

Molecular replacement (MR) is the method of choice for X-ray crystallographic data phasing when structural data of suitable homologues are available. However, MR may fail even in cases of high sequence homology when conformational changes arising for example from ligand binding or different crystallogenic conditions come into play. In this work, the potential of normal-mode analysis as an extension to MR to allow recovery from such drawbacks is demonstrated. Three examples are presented in which screening for MR solutions with templates perturbed in the direction of one or two normal modes allows a valid MR solution to be found where MR using the original template failed to yield a model that could ultimately be refined. It has been shown recently that half of the known protein movements can be modelled by displacing the studied structure using at most two low-frequency normal modes. This suggests that normal-mode analysis has the potential to break tough MR problems in up to 50% of cases. Moreover, even in cases where an MR solution is available, this method can be used to further improve the starting model prior to refinement, eventually reducing the time spent on manual model construction (in particular for low-resolution data sets).

Carrier Proteins↗

PubMed2002

Sequencing, modeling, and selective inhibition of Trypanosoma brucei hexokinase.

For Trypanosoma brucei, a parasite responsible for African sleeping sickness, carbohydrate metabolism is the only source of ATP, and glycolytic enzymes are localized within membrane-bound organelles called glycosomes. Hexokinase, the first enzyme of the glycolytic pathway, was chosen as a target for selective drug design. We have cloned and sequenced the hexokinase gene of T. brucei. In parallel, we have synthesized several inhibitors. Kinetic analysis revealed differences in the binding mode of these compounds toward yeast and T. brucei hexokinases, while the m-bromophenyl glucosamide was found to be selective for T. brucei. The modeled structure of T. brucei hexokinase-inhibitor complex (using the crystal structure of the Schistosoma mansoni hexokinase as a template) allows us to propose a mode of action of this inhibitor for the trypanosome hexokinase and to account for the observed selectivity.

Adenosine Diphosphate↗