Probing the structure of falcipain‐3, a cysteine protease from <i>Plasmodium falciparum</i>: Comparative protein modeling and docking studies

Sabnis, Yogesh; Desai, Prashant; Rosenthal, Philip J.; Avery, Mitchell A.

doi:10.1110/ps.0228103

Cited by 56 publications

(58 citation statements)

References 50 publications

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“…Our results clearly suggest redundancy in the functions performed by the DV plasmepsins. The function of the inactivated gene product may be performed by either one or more of the other three plasmepsins, or possibly the cysteine proteases falcipain 2, 2*, and 3 that are also present in the DV (17,49,50). Parasites in which falcipain 2 has been knocked out also lack any obviously deleterious phenotype, suggesting that the cysteine proteases along the hemoglobin digestion pathway also have redundant functions (51).…”

Section: Discussionmentioning

confidence: 99%

Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy

Omara-Opyene

Moura

Sulsona

et al. 2004

Journal of Biological Chemistry

129

103

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The digestive vacuole plasmepsins PfPM1, PfPM2, PfPM4, and PfHAP (a histoaspartic proteinase) are 4 aspartic proteinases among 10 encoded in the Plasmodium falciparum malarial genome. These have been hypothesized to initiate and contribute significantly to hemoglobin degradation, a catabolic function essential to the survival of this intraerythrocytic parasite. Because of their perceived significance, these plasmepsins have been proposed as potential targets for antimalarial drug development. To test their essentiality, knockout constructs were prepared for each corresponding gene such that homologous recombination would result in two partial, nonfunctional gene copies. Disruption of each gene was achieved, as confirmed by PCR, Southern, and Northern blot analyses. Western and two-dimensional gel analyses revealed the absence of mature or even truncated plasmepsins corresponding to the disrupted gene. Reduced growth rates were observed with PfPM1 and PfPM4 knockouts, indicating that although these plasmepsins are not essential, they are important for parasite development. Abnormal mitochondrial morphology also appeared to accompany loss of PfPM2, and an abundant accumulation of electron-dense vesicles in the digestive vacuole was observed upon disruption of PfPM4; however, those phenotypes only manifested in about a third of the disrupted cells. The ability to compensate for loss of individual plasmepsin function may be explained by close similarity in the structure and active site of these four vacuolar enzymes. Our data imply that drug discovery efforts focused on vacuolar plasmepsins must incorporate measures to develop compounds that can inhibit two or more of this enzyme family.

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Section: Discussionmentioning

confidence: 99%

Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy

Omara-Opyene

Moura

Sulsona

et al. 2004

Journal of Biological Chemistry

129

103

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“…The geometrical and local environmental consistencies of the model were evaluated with ProStat and Profiles-3D (Luthy et al, 1992) modules of InsightII 2000 and the MatchMaker module of Sybyl 6.9. The alignment and identification of the structurally conserved regions (SCRs) and structurally variable regions (SVRs) was carried out as described (Sabnis et al, 2003). Coordinates for the SCRs were assigned from the template molecule.…”

Section: Modeling and Analysis Of The Rhogap Domain Structurementioning

confidence: 99%

“…SVR loop regions were built using the protein loop search protocol (Jones and Thirup, 1986) as available in Composer. The model obtained was then refined by minimization using a similar protocol as described earlier (Sabnis et al, 2003). The final total energy was -5125.146 kJ/mole.…”

Section: Modeling and Analysis Of The Rhogap Domain Structurementioning

confidence: 99%

ARAP2 effects on the actin cytoskeleton are dependent on Arf6-specific GTPase-activating-protein activity and binding to RhoA-GTP

Yoon

Miura

Cuthbert

et al. 2006

Journal of Cell Science

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ARAP2 is a protein that contains both ArfGAP and RhoGAP domains. We found that it is a phosphatidylinositol (3,4,5)-trisphosphate-dependent Arf6 GAP that binds RhoA-GTP but lacks RhoGAP activity. In agreement with the hypothesis that ARAP2 mediates effects of RhoA, endogenous ARAP2 associated with focal adhesions (FAs) and reduction of ARAP2 expression, by RNAi, resulted in fewer FAs and actin stress fibers (SFs). In cells with reduced levels of endogenous ARAP2, FAs and SFs could be restored with wild-type recombinant ARAP2 but not mutants lacking ArfGAP or Rho-binding activity. Constitutively active Arf6 also caused a loss of SFs. The Rho effector ROKα was ineffective in restoring FAs. Conversely, overexpression of ARAP2 did not restore SFs in cells treated with a ROK inhibitor but induced punctate accumulations of paxillin. We conclude that ARAP2 is an Arf6GAP that functions downstream of RhoA to regulate focal adhesion dynamics.

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“…For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002 [24], new potential drug targets for inhibitor development research have been proposed [25,26]. Among these, falcipains (cysteine proteases) from P. falciparum are highly promising target enzymes, which play a key role in hemoglobin degradation in trophozoites [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Teixeira¹,

Gomes²,

Gomes

2011

CMC

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There is a high demand for new drugs against malaria, which takes millions of lives annually. The abuse of classical antimalarials from the late 1940's to the early 1980's has bred resistant parasites, which led to the use of more potent drugs that ended up by refueling the resistance cycle. An example is chloroquine, once highly effective but now virtually useless against malaria.Structure-based rational drug design relies on high-resolution target structures to allow for screening of selective ligands/inhibitors. For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002, enzymes of this lethal malaria parasite species have been increasingly attracting the attention of Medicinal Chemists worldwide as promising drug targets. There is particular emphasis on proteases having key roles on the degradation of host's hemoglobin within the food vacuole of blood-stage parasites, as these depend on such process for their survival. Among such enzymes, Plasmepsins (aspartic proteases) and, especially, Falcipains (cysteine proteases) are highly promising antimalarial drug targets. The present review will focus on the computational approaches made so far towards the unraveling of the structure, function and inhibition of Falcipains that, by virtue of their quite specific features, are excellent targets for highly selective inhibitors.

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Probing the structure of falcipain‐3, a cysteine protease from Plasmodium falciparum: Comparative protein modeling and docking studies

Cited by 56 publications

References 50 publications

Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy

Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy

ARAP2 effects on the actin cytoskeleton are dependent on Arf6-specific GTPase-activating-protein activity and binding to RhoA-GTP

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

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