Sridhar Settu, Bhat Gayathri, Guruprasad Kunchur
Bioinformatics, Centre for Cellular and Molecular Biology, Hyderabad, 500 007 India.
Springerplus. 2013 Oct 26;2:566. doi: 10.1186/2193-1801-2-566. eCollection 2013.
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.
恶性疟原虫（Pf）20S蛋白酶体的三维折叠结构与酿酒酵母20S蛋白酶体相似。由七个不同的α亚基和七个不同的β亚基的两个拷贝组成的28亚基复合物与酵母20S蛋白酶体的等效亚基具有>35%的序列同一性。硼替佐米（万珂®）——一种已知的酵母20S蛋白酶体三个催化亚基β1、β2、β5的抑制剂，可结合到Pf 20S蛋白酶体的等效亚基中，这与实验结果相符。该模型定义了硼替佐米抑制剂在Pf 20S蛋白酶体催化亚基内的结合模式，并为设计Pf 20S蛋白酶体特异性抑制剂提供了结构基础。Pf 20S蛋白酶体催化亚基相对于酵母20S蛋白酶体的替换；Thr21-Ser、Thr22-Ser、Thr31-Ser、Thr35-Asn、Ala49-Ser（在β1亚基中）、Ser20-Ala、Gln22-Glu（β2）和Thr21-Ser、Ala22-Met、Gln53-Leu（β5）可能会影响Pf 20S蛋白酶体相对的类半胱天冬酶样、胰蛋白酶样和糜蛋白酶样活性。Pf 20S蛋白酶体由54个氨基酸残基组成的疟原虫特异性“大”插入序列（在β1亚基中）距离催化位点较远。
