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6 results for “PfCRT”
The knock-down of the chloroquine resistance transporter PfCRT is linked to oligopeptide handling in Plasmodium falciparum
<p class="MsoNormal">The chloroquine resistance transporter, PfCRT, is an essential factor during intraerythrocytic development of the human malaria parasite <em>Plasmodium falciparum</em>. PfCRT resides at the digestive vacuole of the parasite, where hemoglobin taken up by the parasite from its host cell is degraded. PfCRT can acquire several mutations that render PfCRT a drug transporting system expelling compounds targeting hemoglobin degradation from the digestive vacuole. The non-drug related function of PfCRT is less clear, although a recent study has suggested a role in oligopeptide transport based on studies conducted in a heterologous expression system. The uncertainty about the natural function of PfCRT is partly due to a lack of a null mutant and a dearth of functional assays in the parasite. Here, we report on the generation of a conditional PfCRT<em> </em>knock-down mutant in <em>P. falciparum</em>. The mutant accumulated oligopeptides 2 to at least 8 residues in length under knock-down conditions, as shown by comparative global metabolomics. The accumulated oligopeptides were structurally diverse, had an isoelectric point between 4.0 and 5.4 and were electrically neutral or carried a single charge at the digestive vacuolar pH of 5.2. Fluorescently-labeled dipeptides and live cell imaging identified the digestive vacuole as the compartment where oligopeptides accumulated. Our findings suggest a function of PfCRT in oligopeptide transport across the digestive vacuolar membrane in <em>P. falciparum</em> and associated with it a role in nutrient acquisition and the maintenance of the colloid osmotic balance.</p>
Docking of chloroquine and piperaquine to PfCRT_Dd2 and to the PfCRT_Dd2 mutations conferring piperaquine resistance
<p>PDB files of the docking of chloroquine and piperaquine to the PfCRT_Dd2 variant and to the Dd2 mutants investigated</p> <p>reported in the manuscript</p> <p>"PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport"</p> <p>by Guillermo Martin Gomez; Giulia D'Arrigo; Fiona Berger; Cecilia P. Sanchez; Rebecca C. Wade and Michael Lanzer</p> <p>submitted to PLOS Pathogens</p> <p> </p> <p>1. <strong>Dockings.zip </strong>contains <strong>a)</strong> the individual pdb files of the PfCRT_Dd2 variants models prior to preparation with maestro and <strong>b)</strong> sub-folders with the docking results for each PfCRT_Dd2 variant and for PfCRT_7G8</p> <p>2. <strong>Simulations.zip </strong>contains the input file for the simulated systems. Each sub-folder contains:</p> <ul> <li>assembly.pdb - structure of the complex in PDB format</li> <li>assembly.prmtop - topology file in AMBER</li> <li>assembly.inpcrd - coordinates file in AMBER</li> <li>final.pdb - structure after NPT production</li> </ul>
PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport
<p>These data were generated to investigate the effect of point mutations in PfCRT on the kinetics of chloroquine and piperaquine binding and transport. The protein confers resistance to a range of quinoline and quinoline-like antimalarials after the acquisition of certain amino acid substitutions, which occurs as a result of improper antimalarial use. The change in prescription from chloroquine (CQ) to piperaquine (PPQ) in Southeast Asian countries led to the emergence of a ninth mutation over the PfCRT Dd2 isoform, which renders the parasites resistant to piperaquine but re-sensitizes them to chloroquine. Despite structural information, how these individual mutations influence such opposing changes in the parasite's susceptibility to the aforementioned drugs remains unknown. Here, we show by biochemical studies that any of the piperaquine resistance-conferring mutations H97Y, F145I, M343L or G353V, either reduce the affinity of PfCRT Dd2 for CQ (Km) or reduce the efficiency of the transport cycle (Vmax). In parallel, they increase the Vmax, reduce the Km, or do both, in the case of PPQ transport. We also probed the binding cavity of PfCRT Dd2 and that of PfCRT Dd2_F145I, and found that it can readily bind both CQ and PPQ simultaneously, in a partial noncompetitive mechanism. We confirmed the latter finding through molecular docking and molecular dynamics simulations, describing for the first time the binding sites for both drugs in the cavity of PfCRT Dd2. With this, we found that the pocket where CQ binds seems to require an aromatic side chain, which is normally provided by F145, or by Y97 in the PPQ resistance-conferring H97Y mutant. Lastly, we generated an unnatural double mutant carrying both the H97Y and the F145I mutations. The engineered transporter displayed non-Michaelis-Menten kinetics both for CQ and PPQ transport and instead revealed sigmoidal kinetics, typical of proteins that bind substrate cooperatively. We thus provide new insights into the organization of the substrate-binding cavity of PfCRT and into the evolution of PfCRT.</p>
The knock-down of the chloroquine resistance transporter PfCRT is linked to oligopeptide handling in Plasmodium falciparum
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PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport
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Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages
GEO Series GSE205515. Plasmodium falciparum. 13 samples. Type: Expression profiling by array.
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