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Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium.
Structure. 2011 Jul 13; 19(7):919-29.S

Abstract

Plasmodium cysteine proteases are essential for host-cell invasion and egress, hemoglobin degradation, and intracellular development of the parasite. The temporal, site-specific regulation of cysteine-protease activity is a prerequisite for survival and propagation of Plasmodium. Recently, a new family of inhibitors of cysteine proteases (ICPs) with homologs in at least eight Plasmodium species has been identified. Here, we report the 2.6 Å X-ray crystal structure of the C-terminal, inhibitory domain of ICP from P. berghei (PbICP-C) in a 1:1 complex with falcipain-2, an important hemoglobinase of Plasmodium. The structure establishes Plasmodium ICP as a member of the I42 class of chagasin-like protease inhibitors but with large insertions and differences in the binding mode relative to other family members. Furthermore, the PbICP-C structure explains why host-cell cathepsin B-like proteases and, most likely, also the protease-like domain of Plasmodium SERA5 (serine-repeat antigen 5) are no targets for ICP.

Links

Publisher Full Text
linkinghub.elsevier.com
linkinghub.elsevier.com

Authors+Show Affiliations

Hansen G
Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany.
Heitmann A
No affiliation info available
Witt T
No affiliation info available
Li H
No affiliation info available
Jiang H
No affiliation info available
Shen X
No affiliation info available
Heussler VT
No affiliation info available
Rennenberg A
No affiliation info available
Hilgenfeld R
No affiliation info available

MeSH

Amino Acid SequenceAntigens, ProtozoanBinding SitesCathepsin BCloning, MolecularCrystallography, X-RayCysteine EndopeptidasesCysteine Proteinase InhibitorsEscherichia coliMalariaModels, MolecularMolecular Sequence DataPlasmodium bergheiPlasmodium falciparumProtein BindingProtein Structure, TertiaryProtozoan ProteinsRecombinant Fusion ProteinsSequence Alignment

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21742259

Citation

Hansen, Guido, et al. "Structural Basis for the Regulation of Cysteine-protease Activity By a New Class of Protease Inhibitors in Plasmodium." Structure (London, England : 1993), vol. 19, no. 7, 2011, pp. 919-29.
Hansen G, Heitmann A, Witt T, et al. Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium. Structure. 2011;19(7):919-29.
Hansen, G., Heitmann, A., Witt, T., Li, H., Jiang, H., Shen, X., Heussler, V. T., Rennenberg, A., & Hilgenfeld, R. (2011). Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium. Structure (London, England : 1993), 19(7), 919-29. https://doi.org/10.1016/j.str.2011.03.025
Hansen G, et al. Structural Basis for the Regulation of Cysteine-protease Activity By a New Class of Protease Inhibitors in Plasmodium. Structure. 2011 Jul 13;19(7):919-29. PubMed PMID: 21742259.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium. AU - Hansen,Guido, AU - Heitmann,Anna, AU - Witt,Tina, AU - Li,Honglin, AU - Jiang,Hualiang, AU - Shen,Xu, AU - Heussler,Volker T, AU - Rennenberg,Annika, AU - Hilgenfeld,Rolf, PY - 2010/12/22/received PY - 2011/03/28/revised PY - 2011/03/31/accepted PY - 2011/7/12/entrez PY - 2011/7/12/pubmed PY - 2011/11/8/medline SP - 919 EP - 29 JF - Structure (London, England : 1993) JO - Structure VL - 19 IS - 7 N2 - Plasmodium cysteine proteases are essential for host-cell invasion and egress, hemoglobin degradation, and intracellular development of the parasite. The temporal, site-specific regulation of cysteine-protease activity is a prerequisite for survival and propagation of Plasmodium. Recently, a new family of inhibitors of cysteine proteases (ICPs) with homologs in at least eight Plasmodium species has been identified. Here, we report the 2.6 Å X-ray crystal structure of the C-terminal, inhibitory domain of ICP from P. berghei (PbICP-C) in a 1:1 complex with falcipain-2, an important hemoglobinase of Plasmodium. The structure establishes Plasmodium ICP as a member of the I42 class of chagasin-like protease inhibitors but with large insertions and differences in the binding mode relative to other family members. Furthermore, the PbICP-C structure explains why host-cell cathepsin B-like proteases and, most likely, also the protease-like domain of Plasmodium SERA5 (serine-repeat antigen 5) are no targets for ICP. SN - 1878-4186 UR - https://www.unboundmedicine.com/medline/citation/21742259/Structural_basis_for_the_regulation_of_cysteine_protease_activity_by_a_new_class_of_protease_inhibitors_in_Plasmodium_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-2126(11)00186-9 DB - PRIME DP - Unbound Medicine ER -