Fig 1.
Substrates (lanosterol, eburicol and obtusifoliol) and products (ergosterol and cholesterol) of fungal pathogens as well as human and plant orthologues.
* indicates methyl at 14 position.
Fig 2.
Chemical structures of investigated inhibitors.
Fig 3.
Phytopathogen inhibitors complexed in the active site of ScERG11p6×His.
The structures reveal the active site binding orientation of the enantiomers (A) S-TBZ (green carbons, PDB ID:5EAB), (B) R-TBZ (cyan carbons, PDB ID:5EAC), and (C) the superimposition of S-TBZ and R-TBZ, the active site orientation of the enantiomers (D) S-DPZ (magenta carbons, PDB ID:5EAD), (E) R-DPZ (salmon carbons, PDB ID:5EAE), and (F) the superimposition of S-DPZ and R-DPZ. The heme cofactor and selected residues (Y126 and Y140) are shown as sticks. Water-mediated (w743, red sphere) hydrogen bonds are shown as yellow dashed lines. Helix I is shown as a yellow ribbon at the bottom right of each panel. Nitrogen atoms are blue, oxygen red and chlorine green.
Fig 4.
Phytopathogen inhibitors complexed in the active site of ScERG11p6×His.
The structures reveal the binding orientation of (A) FQZ (purple carbons, PDB ID:5EAF), (B) the superimposition of FQZ with FLC (yellow carbons, PDB ID:4WMZ), the binding orientation of (C) PRZ (olive carbons, PDB ID:5EAG) and (D) the superimposition of PRZ with FLC (yellow carbons). The heme cofactor and selected residues (Y126 and Y140) are shown as sticks. Helix I is shown as a grey ribbon at bottom right of each panel. Nitrogen atoms are blue, oxygen red, chlorine green and fluorine pale blue.
Fig 5.
Stereochemistry and binding of the plant pathogen CYP51 inhibitor Difenoconazole.
(A) Stereoisomers of DFC, (2S,4R) - 1-(((2S,4R)-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole; (2S,4S) 1-(((2S,4S)-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole; (2R,4S) 1-(((2R,4S)-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole; (2R,4R) 1-(((2R,4R)-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole. (B) Orientation of DFC stereoisomers (purple carbons, PDB ID:5EAH) bound within the active site of ScErg11p6×His. The heme cofactor and selected residues (Y126, Y140 and F384) are shown as sticks. Hydrogen bonds are shown as yellow dashed lines. Helix I is shown as a grey ribbon at bottom right. (C) Rotated view showing the projection of the 4-methyl substituent towards either Y126 or the heme cofactor. Nitrogen atoms are blue, oxygen red and chlorine green.
Table 1.
MIC50 data for compounds against Saccharomyces cerevisiae strains.
Fig 6.
Azole inhibitor binding to ScErg11p6×His.
Binding saturation curves for (A) S-TBZ (blue) and R-TBZ (red), (B) S-DTZ (blue) and R-DTZ (red), (C) PRZ (blue) and FQZ (red), and (D) S- and R-PTZ in blue and red; with S and R-oxo-PTZ in green and purple respectively showing no binding. Experiments were run at a minimum in duplicate.