Structural Insights into the Activation of P.vivax Plasmepsin

Bernstein, Nina; Cherney, M.M.; Yowell, Charles A.; Dame, John B.; James, Michael N.G.

doi:10.1016/s0022-2836(03)00444-3

Cited by 51 publications

(78 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, 22 triggered a side chain rearrangement of Met 15 and Tyr 17 affecting size and shape of the S3 binding pocket (Figure 2 b). The side chain of Met15 rotated similar to earlier findings [22][23][24] around c 1 and c 2 into a subpocket below S3 and allowed side chain rotation of Tyr 17 and formation of a H-bond with 22.…”

supporting

confidence: 75%

Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV

et al. 2006

View full text Add to dashboard Cite

supporting

confidence: 75%

Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV

et al. 2006

View full text Add to dashboard Cite

“…Cathepsin E, renin, and pepsin A, representing other important human aspartic proteases, exhibit a lower degree of sequence homology. 79,80 Thus, Cat D is commonly used as a marker for cross-inhibition. Comparison between Plm II and Cat D shows a 35% sequence identity and even higher identity was observed at the active site when comparing crystal structures of Plm II and Cat D in complex with pepstatin A.…”

Section: A Selectivity Issuesmentioning

confidence: 99%

Plasmepsins as potential targets for new antimalarial therapy

2006

View full text Add to dashboard Cite

Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum-infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure-activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared.

show abstract

“…All residues belonging to the premature portion of the enzyme were deleted, to obtain a model structure of the enzyme immediately after the cleavage of its premature segment. Missing residues at the flap region were assumed to have an open conformation, since it allows more conformational freedom [20]. They were therefore modelled based on the structure of PM II with an open flap conformation (PDB:2BJU [16]).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

The protonation state of the catalytic aspartates in plasmepsin II

Friedman

Caflisch

2007

FEBS Letters

View full text Add to dashboard Cite

Assigning the correct protonation state to the catalytic residues is essential for a realistic modelling of an enzyme's active site. Plasmepsins are pharmaceutically relevant aspartic proteases involved in haemoglobin degradation by Plasmodium spp. In aspartic proteases, one of the two catalytic aspartates is protonated, while the other is negatively charged. Here, multiple explicit-water molecular dynamics simulations of plasmepsin II, uncomplexed and with a hydroxypropylamine peptidomimetic inhibitor, indicate that protonation of Asp214 favours a stable active site structure. Moreover, the protonation state of the catalytic aspartate has a strong influence on a linear chain of hydrogen bonds with the adjacent side chains.

show abstract

Structural Insights into the Activation of P.vivax Plasmepsin

Cited by 51 publications

References 46 publications

Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV

Achiral, Cheap, and Potent Inhibitors of Plasmepsins I, II, and IV

Plasmepsins as potential targets for new antimalarial therapy

The protonation state of the catalytic aspartates in plasmepsin II

Contact Info

Product

Resources

About