Fig. 6: X-ray crystal structure of CnAcs1-isoxazole complex.
From: Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
A Overall structure of the trimeric CnAcs1-isoxazole 1 complex with the C-terminal domains (CTD) shown in ribbon format. The blue, red, and tan regions of the trimer denote separate monomers comprising the overall trimer. B Mass photometry showing that CnAcs1 is most consistent with a trimer in solution at low concentrations and that the addition of supra-inhibitory of isoxazole 1 does not change the apparent size of the CnAcs1 protein complex. C Schematic comparing “open-TE” (tan) conformation of the CTD observed in the CnAcs1-isoxazole 1 complex to the CTD conformations in the uninhibited APO (blue), AD (green), and TE (orange) forms of the protein. D The region of the protein bound by isoxazole 1 (green) and its position within that pocket. E Overlay of isoxazole 1 (grey) with the bound pose of CoA (turquoise) and an ethyl-AMP inhibitor (yellow) in a previously reported structure of CnAcs1 (ref. 23), showing that 1 interacts with both the CoA pocket and the acetyl portion of the Ac-AMP/alkyl-AMP binding pocket. F The W334 residue functions to open the CoA tunnel by rotating upon CoA binding. The position of W334 CnAcs1-isoxazole 1 (grey) complex overlaps nearly perfectly with that observed in CnAcs1 structures with CoA bound. G Overall of the two CTD conformations in the isoxazole 1-CnAcs1 crystal structure. CTD1 conformation is shown in red, and CTD2 is shown in orange. H Overlap of the positions of isoxazole 1 in the two CTD conformations present in the unit cell of the isoxazole 1-CnAcs1 complex.
