Analysis of bortezomib inhibitor docked within the catalytic subunits of the Plasmodium falciparum 20S proteasome

The three-dimensional fold of Plasmodium falciparum (Pf) 20S proteasome is similar to yeast Saccharomyces cerevisiae 20S proteasome. The twenty eight subunits complex corresponding to two copies of seven distinct α and seven distinct β subunits shares >35% sequence identity with equivalent subunits of the yeast 20S proteasome. Bortezomib (Velcade®) – a known inhibitor of the three catalytic subunits; β1, β2, β5 of the yeast 20S proteasome can bind in the equivalent subunits of the Pf 20S proteasome and is in agreement with experimental results. The model defines the binding mode of the bortezomib inhibitor within the catalytic subunits of the Pf 20S proteasome and provides the structural basis for the design of Pf 20S proteasome-specific inhibitors. The substitutions associated within the catalytic subunits of Pf 20S proteasome relative to yeast 20S proteasome; Thr21-Ser, Thr22-Ser, Thr31-Ser, Thr35-Asn, Ala49-Ser (in β1 subunit), Ser20-Ala, Gln22-Glu (β2) and Thr21-Ser, Ala22-Met, Gln53-Leu (β5) may influence the relative caspase-like, tryptic-like and chymotryptic-like activities of the Pf 20S proteasome. The plasmodia-specific 'large’ insert comprising fifty four amino acid residues (in β1 subunit) of the Pf 20S proteasome is distant from the catalytic sites.