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. doi: 10.1016/j.str.2011.03.025.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigens, Protozoan / chemistry
  • Antigens, Protozoan / metabolism
  • Binding Sites
  • Cathepsin B / chemistry
  • Cathepsin B / metabolism
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / biosynthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / genetics
  • Cysteine Proteinase Inhibitors / pharmacology
  • Escherichia coli
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Models, Molecular
  • Molecular Sequence Data
  • Plasmodium berghei / chemistry
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / enzymology*
  • Plasmodium falciparum / chemistry
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism
  • Recombinant Fusion Proteins / biosynthesis*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • Sequence Alignment

Substances

  • Antigens, Protozoan
  • Cysteine Proteinase Inhibitors
  • Protozoan Proteins
  • Recombinant Fusion Proteins
  • serine repeat antigen 5, Plasmodium falciparum
  • Cysteine Endopeptidases
  • falcipain 2
  • Cathepsin B

Associated data

  • PDB/3PNR