Scytalone dehydratase is a molecular target of inhibitor design efforts aimed at preventing the
fungal disease caused by Magnaporthe grisea. A method for cocrystallization of
enzyme with inhibitors at neutral pH has produced several crystal structures of
enzyme-inhibitor complexes at resolutions ranging from 1.5 to 2.2 A. Four high resolution structures of different
enzyme-inhibitor complexes are described. In contrast to the original X-ray structure of the
enzyme, the four new structures have well-defined electron density for the loop region comprising residues 115-119 and a different conformation between residues 154 and 160. The structure of the
enzyme complex with an aminoquinazoline inhibitor showed that the inhibitor is in a position to form a hydrogen bond with the
amide of the Asn131 side chain and with two water molecules in a fashion similar to the
salicylamide inhibitor in the original structure, thus confirming design principles. The aminoquinazoline structure also allows for a more confident assignment of donors and acceptors in the hydrogen bonding network. The structures of the
enzyme complexes with two dichlorocyclopropane carboxamide inhibitors showed the two
chlorine atoms nearly in plane with the
amide side chain of Asn131. The positions of Phe53 and Phe158 are significantly altered in the new structures in comparison to the two structures obtained from crystals grown at acidic pH. The multiple structures help define the mobility of active site
amino acids critical for catalysis and inhibitor binding.