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Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from Plasmodium falciparum

Nature Structural Biology volume 6, pages 32–37 (1999)Cite this article

Abstract

Proplasmepsin II is the zymogen of plasmepsin II, an aspartic proteinase used by Plasmodium falciparum to digest hemoglobin during the blood stage of malaria. A large shift between the N–domain and the central and C–domains of proplasmepsin II opens the active site cleft, preventing the formation of a functional aspartic proteinase active site. This mode of inhibition of catalytic activity has not been observed in any other aspartic proteinase zymogen. Instead of occluding a pre–formed active site, as in the gastric aspartic proteinase zymogens, the prosegment of proplasmepsin II interacts extensively with the C–domain and serves as a 'harness' to keep the domains apart. Disruption of key salt bridges at low pH may be important in activation.

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Figure 1: Sequence alignment of prosegments of P.
Figure 2: Structural features of proplasmepsin II.
Figure 3: Comparison of proplasmepsin II to plasmepsin II.
Figure 4: Comparison of proplasmepsin II to pepsinogen A.

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Acknowledgements

We wish to thank C. Berry and J. Kay for their contributions to this project, A.M. Silva and J.W. Erickson for sharing their coordinates of plasmepsin II prior to public release, J.F.W. Petersen and K.S. Bateman for data collection at NSLS, N. S. Pannu for assistance with CNS and D. Bur for helpful discussions. N.K.B. is supported by a studentship from the Alberta Heritage Foundation for Medical Research.

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Authors and Affiliations

  1. Department of Biochemistry, Medical Research Group in Protein Structure and Function, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    Nina Khazanovich Bernstein, Maia M. Cherney & Michael N.G. James

  2. F. Hoffmann-La Roche, CH-4002, Basel, Switzerland

    Robert G. Ridley

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  1. Nina Khazanovich Bernstein
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  2. Maia M. Cherney
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  3. Hansruedi Loetscher
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  5. Michael N.G. James
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Correspondence to Michael N.G. James.

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Bernstein, N., Cherney, M., Loetscher, H. et al. Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from Plasmodium falciparum. Nat Struct Mol Biol 6, 32–37 (1999). https://doi.org/10.1038/4905

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