3qs1

Crystal structure of KNI-10006 complex of Plasmepsin I (PMI) from Plasmodium falciparum

spinqualitylabelsall models 3qs1, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qs1 is a 4 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 006, GOL Related: 3qrv Gene: PMI (Plasmodium falciparum) Activity: Plasmepsin I, with EC number 3.4.23.38 Resources: FirstGlance, OCA, RCSB, PDBsum Function [PLM1_PLAFA] Participates in the digestion of the host hemoglobin. Initial cleavage at the hinge region of hemoglobin, than cleaves at other sites, leading to denaturation of the molecule and to further degradation. Publication Abstract from PubMed Plasmepsin I (PMI) is one of the four vacuolar pepsin-like proteases responsible for hemoglobin degradation by the malarial parasite Plasmodium falciparum, and the only one with no crystal structure reported to date. Due to substantial functional redundancy of these enzymes, lack of inhibition of even a single plasmepsin can defeat efforts in creating effective antiparasitic agents. We have now solved crystal structures of the recombinant PMI as apoenzyme and in complex with the potent peptidic inhibitor, KNI-10006, at the resolution of 2.4 and 3.1A, respectively. The apoenzyme crystallized in the orthorhombic space group P2(1)2(1)2(1) with two molecules in the asymmetric unit and the structure has been refined to the final R-factor of 20.7%. The KNI-10006 bound enzyme crystallized in the tetragonal space group P4(3) with four molecules in the asymmetric unit and the structure has been refined to the final R-factor of 21.1%. In the PMI-KNI-10006 complex, the inhibitors were bound identically to all four enzyme molecules, with the opposite directionality of the main chain of KNI-10006 relative to the direction of the enzyme substrates. Such a mode of binding of inhibitors containing an allophenylnorstatine-dimethylthioproline insert in the P1-P1' positions, previously reported in a complex with PMIV, demonstrates the importance of satisfying the requirements for the proper positioning of the functional groups in the mechanism-based inhibitors towards the catalytic machinery of aspartic proteases, as opposed to binding driven solely by the specificity of the individual enzymes. A comparison of the structure of the PMI-KNI-10006 complex with the structures of other vacuolar plasmepsins identified the important differences between them and may help in the design of specific inhibitors targeting the individual enzymes. Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum.,Bhaumik P, Horimoto Y, Xiao H, Miura T, Hidaka K, Kiso Y, Wlodawer A, Yada RY, Gustchina A J Struct Biol. 2011 Apr 20. PMID:21521654 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Plasmepsin

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