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pepsin-like aspartic proteases

NOT Open Access | Activation mechanism of plasmepsins, pepsin-like aspartic proteases from Plasmodium, follows a unique trans-activation pathway

May 13, 2020 - 13:54 -- NOT Open Access
Rathore I, Mishra V, Patel C, Xiao H, Gustchina A, Wlodawer A, Yada RY, Bhaumik P
FEBS J. 2020 May 9

Plasmodium parasites that cause malaria produce plasmepsins (PMs), pepsin‐like aspartic proteases that are important antimalarial drug targets due to their role in host hemoglobin degradation. The enzymes are synthesized as inactive zymogens (pro‐PMs) and the mechanism of their conversion to the active, mature forms has not been clearly elucidated. Our structural investigations of vacuolar pro‐PMs with truncated prosegment (pro‐tPMs) reveal that the formation of the S‐shaped dimer is their innate property. Further structural studies, biochemical analysis, and molecular dynamics simulations indicate that disruption of the Tyr‐Asp loop (121p‐4), coordinated with the movement of the loop L1 (237‐247) and helix H2 (101p‐113p) are responsible for the extension of the pro‐mature region (harboring the cleavage site).

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