title: Structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in Plasmodium.
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.
authors: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany.
authors: Guido
authors: G
authors: Hansen
authors: Anna
authors: A
authors: Heitmann
authors: Tina
authors: T
authors: Witt
authors: Honglin
authors: H
authors: Li
authors: Hualiang
authors: H
authors: Jiang
authors: Xu
authors: X
authors: Shen
authors: Volker T
authors: VT
authors: Heussler
authors: Annika
authors: A
authors: Rennenberg
authors: Rolf
authors: R
authors: Hilgenfeld
mesh_terms: D000595:Amino Acid Sequence; D000953:Antigens, Protozoan / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002401:Cathepsin B / Q000737:chemistry / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D004926:Escherichia coli; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010962:Plasmodium berghei / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D016415:Sequence Alignment
chemical_list: D000953:Antigens, Protozoan; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; C480167:serine repeat antigen 5, Plasmodium falciparum; D003546:Cysteine Endopeptidases; C416224:falcipain 2; D002401:Cathepsin B