Taxonomic group: fungi /
Organ / tissue: cell wall
NCBI PubMed ID: 29164827Publication DOI: 10.1002/cmdc.201700720Journal NLM ID: 101259013Publisher: Wiley-VCH
Correspondence: Delso I <idelso
unizar.es>; Hurtado-Guerrero R <rhurtado
bifi.es>; Merino P <pmerino
unizar.es>
Institutions: Fundacion ARAID, Zaragoza, Spain, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, Zaragoza, Spain, Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Campus Rio Ebro, Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland
Fungal β-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X-ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation-π and face-to-face π-π interactions. The lead compound is capable of inhibiting AfGel4 with an IC50 value of 42 μm.
carbohydrates, Oligosaccharides, Glycomimetics, Aspergillus fumigatus, transglycosylases
Structure type: structural motif or average structure
Location inside paper: p. 128, column 1, paragraph 1
Trivial name: β-1,3-glucan
Compound class: EPS, O-polysaccharide, cell wall polysaccharide, glucan
Contained glycoepitopes: IEDB_1397514,IEDB_142488,IEDB_146664,IEDB_153543,IEDB_158555,IEDB_161166,IEDB_2278476,IEDB_2278477,IEDB_558869,IEDB_857743,IEDB_983931,SB_192
Enzymes that release or process the structure: Gelp, Gasp, Phrp
Biosynthesis and genetic data: biochemical data, genetic data
3D data: computer modeling
NCBI Taxonomy refs (TaxIDs): 4751Reference(s) to other database(s): GTC:G51056AN
Show glycosyltransferases
There is only one chemically distinct structure:
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