5O9Q

Crystal structure of ScGas2 in complex with compound 6

Summary for 5O9Q

• Entry DOI: 10.2210/pdb5o9q/pdb
• Descriptor: 1,3-beta-glucanosyltransferase GAS2, beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose, (2~{R},3~{S},4~{S},5~{R},6~{S})-2-(hydroxymethyl)-6-[(2~{R},3~{R},4~{S},5~{R},6~{S})-2-(hydroxymethyl)-6-[(2~{R},3~{R},4~{S},5~{R},6~{R})-2-(hydroxymethyl)-3,5-bis(oxidanyl)-6-[4-(phenylmethoxymethyl)-1,2,3-triazol-1-yl]oxan-4-yl]oxy-3,5-bis(oxidanyl)oxan-4-yl]oxy-oxane-3,4,5-triol, ... (4 entities in total)
• Functional Keywords: aspergillus fumigatus, afgel4, scgas2, transglycosylases, glucanosyltransferases, cell wall remodeling, fungal cell wall, transferase
• Biological source: Saccharomyces cerevisiae S288c
• Cellular location: Cell membrane ; Lipid-anchor, GPI-anchor : Q06135
• Total number of polymer chains: 1
• Total formula weight: 63606.07

Authors

Delso, I.,Valero-Gonzalez, J.,Gomollon-Bel, F.,Castro-Lopez, J.,Fang, W.,Navratilova, I.,Van Aalten, D.,Tejero, T.,Merino, P.,Hurtado-Guerrero, R. (deposition date: 2017-06-20, release date: 2018-05-02, Last modification date: 2024-11-13)

Primary citation

Delso, I.,Valero-Gonzalez, J.,Gomollon-Bel, F.,Castro-Lopez, J.,Fang, W.,Navratilova, I.,van Aalten, D.M.F.,Tejero, T.,Merino, P.,Hurtado-Guerrero, R.
Inhibitors against Fungal Cell Wall Remodeling Enzymes.
ChemMedChem, 13:128-132, 2018

PubMed Abstract: 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 IC value of 42 μm.

PubMed: 29164827
DOI: 10.1002/cmdc.201700720

Experimental method

X-RAY DIFFRACTION (1.4 Å)