Hemoglobin-degrading Plasmepsin II Is Active as a Monomer

Liu, Jun; Istvan, Eva S.; Goldberg, Daniel E.

doi:10.1074/jbc.m608535200

Cited by 15 publications

(13 citation statements)

References 32 publications

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“…Several biochemical and crystallographic studies have attempted to analyze the oligomeric forms of plasmepsins [52,53], but the significance of oligomerization of these enzymes, if any, has not been fully established as yet. It has been shown that monomeric forms of the enzymes are responsible for their activity [52].…”

Section: Structural Features Of Plasmepsinsmentioning

confidence: 99%

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Structural studies of vacuolar plasmepsins

Bhaumik

Gustchina

Wlodawer

2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium species (P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes ten PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), four of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50-79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium species. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure-function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15 years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs.

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Section: Structural Features Of Plasmepsinsmentioning

confidence: 99%

“…It has been shown that monomeric forms of the enzymes are responsible for their activity [52]. Since creation of crystal lattices always involves intermolecular interactions, it is not always easy to determine whether the oligomeric states observed in the crystals are meaningful or not.…”

Section: Structural Features Of Plasmepsinsmentioning

confidence: 99%

Structural studies of vacuolar plasmepsins

Bhaumik

Gustchina

Wlodawer

2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…Residues V105 and T108 are located in a flap of an interior pocket and only establish contacts with a specific nonpeptide achiral inhibitor. Residue L242 is located in the L3 loop,31 recently described as an essential region in cleaving intact hemoglobin 33. Residue Q275 is situated in the small β1024 neighbor to the L4 loop,31 while residues Y17, L191 and T298 belong to well‐defined pockets lining the binding site cavity.…”

Section: Introductionmentioning

confidence: 99%

Predicting functional residues in Plasmodium falciparum plasmepsins by combining sequence and structural analysis with molecular dynamics simulations

et al. 2008

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Plasmepsins are aspartic proteases involved in the initial steps of the hemoglobin degradation pathway, a critical stage in the Plasmodium falciparum life cycle during human infection. Thus, they are attractive targets for novel therapeutic compounds to treat malaria, which remains one of the world's biggest health problems. The three-dimensional structures available for P. falciparum plasmepsins II and IV make structure-based drug design of antimalarial compounds that focus on inhibiting plasmepsins possible. However, the structural flexibility of the plasmepsin active site cavity combined with insufficient knowledge of the functional residues and of those determining the specificity of parasitic enzymes is a drawback when designing specific inhibitors. In this study, we have combined a sequence and structural analysis with molecular dynamics simulations to predict the functional residues in P. falciparum plasmepsins. The careful analysis of X-ray structures and 3D models carried out here suggests that residues Y17, V105, T108, L191, L242, Q275, and T298 are important for plasmepsin function. These seven amino acids are conserved across the malarial strains but not in human aspartic proteases. Residues V105 and T108 are localized in a flap of an interior pocket and they only establish contacts with a specific non-peptide achiral inhibitor. We also observed a rapid conformational change in the L3 region of plasmepsins that closes the active site of the enzyme, which explains earlier experimental findings. These results shed light on the role of V105 and T108 residues in plasmepsin specificities, and they should be useful in structure-based design of novel, selective inhibitors that may serve as antimalarial drugs.

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“…In addition, structures from other species of Plasmodium have been reported: one of PlmIV from P. malariae (PDB: 2ANL) and two from P. vivax (PDB: 1QS8, 1MIQ). It should be noted that Plms form homodimers with extensive interfaces in most of the known X-ray structures; conversely, an experimental study revealed that PlmII exists mainly as a monomer in solution, and that the monomer is fully functional for catalysis [52]. Therefore, practically all the in silico studies of these enzymes use the monomer structure as target [53–58]; with the drawback, these proteins need an extensive computational work to relax the regions of the protein buried in the dimmer.…”

Section: Evolution Of Plasmepsins As Chemotherapeutic Targetsmentioning

confidence: 99%

“…Residues V105 and T108 are located in a loop of an interior pocket and only establish contacts with a specific nonpeptide achiral inhibitor, as was illustrated analyzing the PlmII-inhibitor X-ray structures. Residue L242 is located in the L3 loop, recently described as an essential region in cleaving intact hemoglobin [73]. Residue Q275 is situated in a small β -strand in close vicinity to the L4 loop.…”

Section: Sequence and Structure Analyses Of Plms Familymentioning

confidence: 99%

Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design

Gil

Valiente

Pascutti³

et al. 2011

Journal of Tropical Medicine

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The development of efficient and selective antimalariais remains a challenge for the pharmaceutical industry. The aspartic proteases plasmepsins, whose inhibition leads to parasite death, are classified as targets for the design of potent drugs. Combinatorial synthesis is currently being used to generate inhibitor libraries for these enzymes, and together with computational methodologies have been demonstrated capable for the selection of lead compounds. The high structural flexibility of plasmepsins, revealed by their X-ray structures and molecular dynamics simulations, made even more complicated the prediction of putative binding modes, and therefore, the use of common computational tools, like docking and free-energy calculations. In this review, we revised the computational strategies utilized so far, for the structure-function relationship studies concerning the plasmepsin family, with special focus on the recent advances in the improvement of the linear interaction estimation (LIE) method, which is one of the most successful methodologies in the evaluation of plasmepsin-inhibitor binding affinity.

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Hemoglobin-degrading Plasmepsin II Is Active as a Monomer

Cited by 15 publications

References 32 publications

Structural studies of vacuolar plasmepsins

Structural studies of vacuolar plasmepsins

Predicting functional residues in Plasmodium falciparum plasmepsins by combining sequence and structural analysis with molecular dynamics simulations

Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design

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