Pepsinogen-like activation intermediate of plasmepsin II revealed by molecular dynamics analysis

TitlePepsinogen-like activation intermediate of plasmepsin II revealed by molecular dynamics analysis
Publication TypeJournal Article
Year of Publication2008
AuthorsFriedman R., Caflisch A.
JournalProteins: Structure, Function, and Bioinformatics
Volume73
Issue4
Pagination814-827
Date Published2008 Dec
Type of ArticleResearch Article
ISSN1097-0134
KeywordsAspartic Acid Endopeptidases, Catalysis, Catalytic Domain, Computer Simulation, Enzyme Activation, Enzyme Precursors, Hydrogen Bonding, Models, Molecular, Pepsinogens, Pliability, Protein Structure, Secondary, Protein Structure, Tertiary, Protozoan Proteins, Thermodynamics
Abstract

Plasmepsins are pharmaceutically relevant aspartic proteases involved in haemoglobin degradation by the malaria causing parasites Plasmodium spp. They are translated as inactive proenzymes, with an elongated prosegment. On prosegment cleavage, plasmepsins undergo a series of hitherto unresolved conformational changes before becoming active. Here, the flexibility of plasmepsin and proplasmepsin and the activation process are investigated by multiple explicit water molecular dynamics simulations. The large N-terminal displacement and the interdomain shift from the proenzyme structure to active plasmepsin are promoted by essential dynamics sampling. An intermediate, stabilized by electrostatic interactions between the catalytic dyad and the N-terminus of mature plasmepsin, is observed along all activation trajectories. Notably, the stabilizing interactions in the activation intermediate of plasmepsin are similar to those in the X-ray structure of pepsinogen. In particular, the catalytic aspartates act as hydrogen bond acceptors for the N-terminal amino group and the Ser2 hydroxyl in plasmepsin, and the side chains of Lys36pro and Tyr9 in pepsinogen. The simulation results are used to suggest in vitro experiments to test the conformational transitions involved in the maturation of plasmepsin, and design small-molecule inhibitors.

DOI10.1002/prot.22105
pubindex

0103

Alternate JournalProteins
PubMed ID18498105
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