Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble

The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti-influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti-influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS-Map) to identify putative ‘hot spots’ within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40-ns MD simulations, CS-Map was utilized to assess the ability of small, solvent-sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150- and 430-loop regions. Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain

Catalytic mechanisms and reaction intermediates along the hydrolytic pathway of a plant β-D-glucan glucohydrolases: crystallographic, chemical and quantum mechanical analyses

International audienc

Eigenfunctions of open-shell molecules: experimental spin densities in hexafluorochromate(3-) and tetrachlorocobaltate(2-)

No abstract availabl

Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size

Journal of Medical Genetics5010666 - 673JMDG

A common protein fold and similar active site in two distinct families of β-glycanases

International audienceThe structure of Clostridium thermocellum endoglucanase CelC, a member of the largest cellulase family (family A), has been determined at 2.15 A resolution. The protein folds into an (alpha/beta)8 barrel, with a deep active-site cleft generated by the insertion of a helical subdomain. The structure of the catalytic core of xylanase XynZ, which belongs to xylanase family F, has been determined at 1.4 A resolution. In spite of significant differences in substrate specificity and structure (including the absence of the helical subdomain), the general polypeptide folding pattern, architecture of the active site and catalytic mechanism of XynZ and CelC are similar, suggesting a common evolutionary origin

Structure-function relationships of beta-D-glucan endo- and exohydrolases from higher plants

(1→3),(1→4)-β-D-Glucans represent an important component of cell walls in the Poaceae family of higher plants. A number of glycoside endo- and exohydrolases is required for the depolymerization of (1→3),(1→4)-β-Dglucans in germinated grain or for the partial hydrolysis of the polysaccharide in elongating vegetative tissues. The enzymes include (1→3),(1→4)-β-D-glucan endohydrolases (EC 3.2.1.73), which are classified as family 17 glycoside hydrolases, (1→4)-β-D-glucan glucohydrolases (family 1) and β-D-glucan exohydrolases (family 3). Kinetic analyses of hydrolytic reactions enable the definition of action patterns, the thermodynamics of substrate binding, and the construction of subsite maps. Mechanism-based inhibitors and substrate analogues have been used to study the spatial orientation of the substrate in the active sites of the enzymes, at the atomic level. The inhibitors and substrate analogues also allow us to define the catalytic mechanisms of the enzymes and to identify catalytic amino acid residues. Three-dimensional structures of (1→3),(1→4)-β-D-glucan endohydrolases, (1→4)- β-D-glucan glucohydrolases and β-D-glucan exohydrolases are available or can be reliably modelled from the crystal structures of related enzymes. Substrate analogues have been diffused into crystals for solving of the threedimensional structures of enzyme-substrate complexes. This information provides valuable insights into potential biological roles of the enzymes in the degradation of the barley (1→3),(1→4)-β-D-glucans during endosperm mobilization and in cell elongation.Maria Hrmova and Geoffrey B. Finche