Figure 9.

Malarial aminopeptidase PfA-M1 in complex with a bestatin-derived inhibitor. (A) PfA-M1 comprises four domains, whereby the inhibitor (yellow sphere model) is located in the center of the catalytic domain cat(II). (B) The catalytic Zn²⁺ (grey sphere) is coordinated by His496, His500 and Glu519. Glu497 activates the catalytic water molecule and belongs to the metalloprotease motif HEXXH, which is also present in MMPs, whereas the other side chains bind substrates. (C) The inhibitor consists of a modified statin (Sta) with a para-methoxy-Phe side chain instead of a Leu. Its amino group is bound by Glu319 and Glu463 as well as by Tyr580. Though the Sta derivative binds the S1 pocket, Leu is preferred in the S1′ subsite.