scholarly journals Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Lionel Ballut ◽  
Sébastien Violot ◽  
Santosh Shivakumaraswamy ◽  
Lakshmi Prasoona Thota ◽  
Manu Sathya ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Active Site ◽  
Gmp Synthetase ◽  
Domain Rotation

scholarly journals Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Changyao Li ◽  
Yan Chai ◽  
Hao Song ◽  
Changjiang Weng ◽  
Jianxun Qi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mycobacterium Tuberculosis ◽  
High Resolution ◽  
Drug Design ◽  
Active Site ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Fever Virus ◽  
Potential Drug ◽  
Content Type

ABSTRACT E165R, a highly specific dUTP nucleotidohydrolase (dUTPase) encoded by the African swine fever virus (ASFV) genome, is required for productive replication of ASFV in swine macrophages. Here, we solved the high-resolution crystal structures of E165R in its apo state and in complex with its product dUMP. Structural analysis explicitly defined the architecture of the active site of the enzyme as well as the interaction between the active site and the dUMP ligand. By comparing the ASFV E165R structure with dUTPase structures from other species, we found that the active site of E165R is highly similar to those of dUTPases from Mycobacterium tuberculosis and Plasmodium falciparum, against which small-molecule chemicals have been developed, which could be the potential drug or lead compound candidates for ASFV. Our results provide important basis for anti-ASFV drug design by targeting E165R. IMPORTANCE African swine fever virus (ASFV), an Asfivirus affecting pigs and wild boars with up to 100% case fatality rate, is currently rampaging throughout China and some other countries in Asia. There is an urgent need to develop therapeutic and preventive reagents against the virus. Our crystallographic and biochemical studies reveal that ASFV E165R is a member of trimeric dUTP nucleotidohydrolase (dUTPase) family that catalyzes the hydrolysis of dUTP into dUMP. Our apo-E165R and E165R-dUMP structures reveal the constitutive residues and the configuration of the active center of this enzyme in rich detail and give evidence that the active center of E165R is very similar to that of dUTPases from Plasmodium falciparum and Mycobacterium tuberculosis, which have already been used as targets for designing drugs. Therefore, our high-resolution structures of E165R provide useful structural information for chemotherapeutic drug design.

scholarly journals The interactome of 2-Cys peroxiredoxins in Plasmodium falciparum

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Christina Brandstaedter ◽  
Claire Delahunty ◽  
Susanne Schipper ◽  
Stefan Rahlfs ◽  
John R. Yates ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Active Site ◽  
Cellular Protein ◽  
Mitochondrial Proteins ◽  
Target Proteins ◽  
Cellular Processes ◽  
Mixed Disulfide ◽  
Functional Analyses ◽  
Cell Proteome ◽  
Active Site Mutants

Abstract Peroxiredoxins (Prxs) are crucially involved in maintaining intracellular H2O2 homeostasis via their peroxidase activity. However, more recently, this class of proteins was found to also transmit oxidizing equivalents to selected downstream proteins, which suggests an important function of Prxs in the regulation of cellular protein redox relays. Using a pull-down assay based on mixed disulfide fishing, we characterized the thiol-dependent interactome of cytosolic Prx1a and mitochondrial Prx1m from the apicomplexan malaria parasite Plasmodium falciparum (Pf). Here, 127 cytosolic and 20 mitochondrial proteins that are components of essential cellular processes were found to interact with PfPrx1a and PfPrx1m, respectively. Notably, our data obtained with active-site mutants suggests that reducing equivalents might also be transferred from Prxs to target proteins. Initial functional analyses indicated that the interaction with Prx can strongly impact the activity of target proteins. The results provide initial insights into the interactome of Prxs at the level of a eukaryotic whole cell proteome. Furthermore, they contribute to our understanding of redox regulatory principles and thiol-dependent redox relays of Prxs in subcellular compartments.

scholarly journals Functional and structural resilience of the active site loop in the evolution of Plasmodium lactate dehydrogenase

2018 ◽  
Author(s):  
Jacob D. Wirth ◽  
Jeffrey I. Boucher ◽  
Joseph R. Jacobowitz ◽  
Scott Classen ◽  
Douglas L. Theobald
Keyword(s):  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Malate Dehydrogenase ◽  
Active Site ◽  
Drug Target ◽  
Insertion Sequence ◽  
High Potential ◽  
Ldh Activity

AbstractThe malarial pathogen Plasmodium falciparum (Pf) is a member of the Apicomplexa, which independently evolved a highly specific lactate dehydrogenase (LDH) from an ancestral malate dehydrogenase (MDH) via a five-residue insertion in a key active site loop. PfLDH is widely considered an attractive drug target due to its unique active site. Apicomplexan loop conservation suggests that a particular insertion sequence was required to evolve LDH specificity, and we previously showed (Boucher 2014) that a tryptophan in the insertion, W107f, is essential for activity and specificity. However, the roles of other residues in the loop are currently unknown. Here we show that PfLDH activity is remarkably resilient to radical perturbations of both loop identity and length. Thus, alternative insertions could have evolved LDH specificity as long as they contained a tryptophan in the proper location. PfLDH therefore has high potential to develop resistance to drugs that target its distinctive active site.

scholarly journals DOCKING STUDIES OF AMINOHYDANTOIN DERIVATIVES AS ANTIMALARIAL AGENTS

2018 ◽  
Vol 8 (5-s) ◽  
pp. 322-326
Author(s):  
Pooja Mali ◽  
Shourya Pratap ◽  
Raghvendra S. Badhauria ◽  
Himanshu Gurjar
Keyword(s):  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Active Site ◽  
Docking Study ◽  
Docking Studies ◽  
Binding Interaction ◽  
Antimalarial Agents ◽  
Rank Score ◽  
Observable Data ◽  
Virtual Platform

Objective: Docking studies of aminohydantoin derivatives as antimalarial agents. A novel derivative of aminohydantoins was selected from the literature. Method: in-silco studies using docking methodology. The compounds were sketched and energy minimized using Chem draw ultra and Chem 3D ultra respectively. Further, the compounds were docked into Plasmodium falciparum transferase inhibitor (3L7) using Molegro Virtual Platform. Twenty eight compounds were docked into the active site of Pf-lactate dehydrogenase cavity and all of them found to have similar binding interactions of a co-crystalized ligand. Result: The compounds were showed good docking score like moldock score and re-rank score. The finding of docking studies shows a typical molecular interaction pattern with lactate dehydrogenase. The binding interaction information derived from these molecules will be useful in future antimalarial agent design. Conclusion: From the docking study, it was observed that ligands bind to the electrostatic, hydrophobic clamp formed by the residues Asp 76(B), Tyr 190(B), Tyr 80(B) and Lys 72(B) which play an important role for Plasmodium falciparum inhibition.   The binding affinity, grid calculation and RMSD percentage lower and upper   parameters were calculated.   Hence, the observable data indicated that, above compounds can serve as good leads for further modification and optimization in the of treatment malaria. Keywords: Molegro, Chemdraw, aminohydantoins and docking, studies as Plasmodium falciparum, 4RAO, moldock score.

Plasmodium falciparum, P. vivax,andP. malariae:A Comparison of the Active Site Properties of Plasmepsins Cloned and Expressed from Three Different Species of the Malaria Parasite

1997 ◽  
Vol 87 (3) ◽  
pp. 185-193 ◽  
Author(s):  
Jennifer Westling ◽  
Charles A. Yowell ◽  
Pavel Majer ◽  
John W. Erickson ◽  
John B. Dame ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Active Site ◽  
Malaria Parasite

Structural and active site analysis of plasmepsins of Plasmodium falciparum: Potential anti-malarial targets

2005 ◽  
Vol 37 (1-2) ◽  
pp. 73-84 ◽  
Author(s):  
Rayavarapu Bhargavi ◽  
G. Madhavi Sastry ◽  
U. Suryanarayana Murty ◽  
G. Narahari Sastry
Keyword(s):  
Plasmodium Falciparum ◽  
Active Site ◽  
Site Analysis

Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 2.25 Å resolution reveals intriguing extra electron density in the active site

2005 ◽  
Vol 62 (3) ◽  
pp. 570-577 ◽  
Author(s):  
Mark A. Robien ◽  
Jürgen Bosch ◽  
Frederick S. Buckner ◽  
Wesley C. E. Van Voorhis ◽  
Elizabeth A. Worthey ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Plasmodium Falciparum ◽  
Electron Density ◽  
Active Site ◽  
Extra Electron
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