Fig. 8: Mutations in the CaAcs2 CoA binding pocket increase inhibition by isoxazole 1 and MMV084978.
From: Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
A CoA binding site of CaAcs2 with isoxazole 1 was modeled based on structural alignment with the CnAcs1-isoxazole 1 complex. B The highlighted residues in CaAcs2 were mutated to the corresponding CnAcs1 residues to create CaCnAcs2. C Comparison of CaAcs2 and CaCnAcs2 inhibition by isoxazole 1 (R2 for CaCnAcs2 fit: 0.74). D CnM445QAcs1 mutant is inhibited by isoxazole 1 with similar potency; R2 = 0.93 for CnAcs1 and R2 = 0.82 for CnM445QAcs1. E The potency of MMV084978 is increased in CaCnAcs2 relative to CaAcs2 (R2 = 0.94). Error bars indicate the standard deviation of two independent replicates. F Overlap of 1 (grey) and MMV084978 (magenta) docked into CnAcs1 with binding affinity data (kcal/mol). Source data are provided as a Source data file.
