Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum
| Autor: | Talapady N. Bhat, Kathryn E. Luker, P Maier, A. Y. Lee, P.J. Collins, Raul E. Cachau, John W. Erickson, Ilya Y. Gluzman, Abelardo M. Silva, Daniel E. Goldberg, Susan E. Francis, Anna Oksman, S V Gulnik, Jack R. Collins |
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| Rok vydání: | 1996 |
| Předmět: |
Molecular Sequence Data
Plasmodium falciparum Molecular Conformation Protozoan Proteins Plasmepsin Biology Crystallography X-Ray Cathepsin D Protein Structure Secondary Substrate Specificity Hemoglobins chemistry.chemical_compound Plasmepsin II Chloroquine parasitic diseases Escherichia coli medicine Animals Aspartic Acid Endopeptidases Humans Protease Inhibitors Amino Acid Sequence Cloning Molecular Conserved Sequence chemistry.chemical_classification Multidisciplinary Sequence Homology Amino Acid Mefloquine biology.organism_classification Recombinant Proteins Enzyme chemistry Biochemistry Plasmepsin I Pepstatin Research Article medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 93:10034-10039 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.93.19.10034 |
| Popis: | Plasmodium falciparum is the major causative agent of malaria, a disease of worldwide importance. Resistance to current drugs such as chloroquine and mefloquine is spreading at an alarming rate, and our antimalarial armamentarium is almost depleted. The malarial parasite encodes two homologous aspartic proteases, plasmepsins I and II, which are essential components of its hemoglobin-degradation pathway and are novel targets for antimalarial drug development. We have determined the crystal structure of recombinant plasmepsin II complexed with pepstatin A. This represents the first reported crystal structure of a protein from P. falciparum. The crystals contain molecules in two different conformations, revealing a remarkable degree of interdomain flexibility of the enzyme. The structure was used to design a series of selective low molecular weight compounds that inhibit both plasmepsin II and the growth of P. falciparum in culture. |
| Databáze: | OpenAIRE |
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