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The natural function of the malaria parasite’s chloroquine resistance transporter
by
Lancaster, Nicole S.
, Shafik, Sarah H.
, McConville, Malcolm J.
, Richards, Sashika N.
, Hogg, Simon J.
, Martin, Rowena E.
, Summers, Robert L.
, Llinás, Manuel
, Cobbold, Simon A.
, Barkat, Kawthar
in
13/109
/ 14
/ 14/1
/ 14/63
/ 631/326/417/1716
/ 631/326/417/2552
/ 631/45/320
/ 631/80/642/1624
/ 64
/ 64/114
/ 82/1
/ 82/58
/ 82/80
/ 9/10
/ Amino acids
/ Animals
/ Antimalarials - pharmacology
/ Biological Transport, Active
/ Chloroquine
/ Chloroquine - pharmacology
/ Cytosol
/ Drug development
/ Drug resistance
/ Drug Resistance - genetics
/ Erythrocytes
/ Female
/ Host-Parasite Interactions - genetics
/ Host-Parasite Interactions - physiology
/ Humanities and Social Sciences
/ Humans
/ Ions
/ Malaria
/ Malaria, Falciparum - drug therapy
/ Malaria, Falciparum - metabolism
/ Malaria, Falciparum - parasitology
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Metabolites
/ Models, Biological
/ multidisciplinary
/ Multidrug resistance
/ Mutant Proteins - genetics
/ Mutant Proteins - metabolism
/ Mutation
/ Oligopeptides - metabolism
/ Oocytes - metabolism
/ Osmotic stress
/ Parasite resistance
/ Parasites
/ Peptides
/ Plasmodium falciparum
/ Plasmodium falciparum - drug effects
/ Plasmodium falciparum - genetics
/ Plasmodium falciparum - metabolism
/ Protein Transport
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Residues
/ Science
/ Science (multidisciplinary)
/ Substrates
/ Vector-borne diseases
/ Xenopus laevis
2020
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The natural function of the malaria parasite’s chloroquine resistance transporter
by
Lancaster, Nicole S.
, Shafik, Sarah H.
, McConville, Malcolm J.
, Richards, Sashika N.
, Hogg, Simon J.
, Martin, Rowena E.
, Summers, Robert L.
, Llinás, Manuel
, Cobbold, Simon A.
, Barkat, Kawthar
in
13/109
/ 14
/ 14/1
/ 14/63
/ 631/326/417/1716
/ 631/326/417/2552
/ 631/45/320
/ 631/80/642/1624
/ 64
/ 64/114
/ 82/1
/ 82/58
/ 82/80
/ 9/10
/ Amino acids
/ Animals
/ Antimalarials - pharmacology
/ Biological Transport, Active
/ Chloroquine
/ Chloroquine - pharmacology
/ Cytosol
/ Drug development
/ Drug resistance
/ Drug Resistance - genetics
/ Erythrocytes
/ Female
/ Host-Parasite Interactions - genetics
/ Host-Parasite Interactions - physiology
/ Humanities and Social Sciences
/ Humans
/ Ions
/ Malaria
/ Malaria, Falciparum - drug therapy
/ Malaria, Falciparum - metabolism
/ Malaria, Falciparum - parasitology
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Metabolites
/ Models, Biological
/ multidisciplinary
/ Multidrug resistance
/ Mutant Proteins - genetics
/ Mutant Proteins - metabolism
/ Mutation
/ Oligopeptides - metabolism
/ Oocytes - metabolism
/ Osmotic stress
/ Parasite resistance
/ Parasites
/ Peptides
/ Plasmodium falciparum
/ Plasmodium falciparum - drug effects
/ Plasmodium falciparum - genetics
/ Plasmodium falciparum - metabolism
/ Protein Transport
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Residues
/ Science
/ Science (multidisciplinary)
/ Substrates
/ Vector-borne diseases
/ Xenopus laevis
2020
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The natural function of the malaria parasite’s chloroquine resistance transporter
by
Lancaster, Nicole S.
, Shafik, Sarah H.
, McConville, Malcolm J.
, Richards, Sashika N.
, Hogg, Simon J.
, Martin, Rowena E.
, Summers, Robert L.
, Llinás, Manuel
, Cobbold, Simon A.
, Barkat, Kawthar
in
13/109
/ 14
/ 14/1
/ 14/63
/ 631/326/417/1716
/ 631/326/417/2552
/ 631/45/320
/ 631/80/642/1624
/ 64
/ 64/114
/ 82/1
/ 82/58
/ 82/80
/ 9/10
/ Amino acids
/ Animals
/ Antimalarials - pharmacology
/ Biological Transport, Active
/ Chloroquine
/ Chloroquine - pharmacology
/ Cytosol
/ Drug development
/ Drug resistance
/ Drug Resistance - genetics
/ Erythrocytes
/ Female
/ Host-Parasite Interactions - genetics
/ Host-Parasite Interactions - physiology
/ Humanities and Social Sciences
/ Humans
/ Ions
/ Malaria
/ Malaria, Falciparum - drug therapy
/ Malaria, Falciparum - metabolism
/ Malaria, Falciparum - parasitology
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Metabolites
/ Models, Biological
/ multidisciplinary
/ Multidrug resistance
/ Mutant Proteins - genetics
/ Mutant Proteins - metabolism
/ Mutation
/ Oligopeptides - metabolism
/ Oocytes - metabolism
/ Osmotic stress
/ Parasite resistance
/ Parasites
/ Peptides
/ Plasmodium falciparum
/ Plasmodium falciparum - drug effects
/ Plasmodium falciparum - genetics
/ Plasmodium falciparum - metabolism
/ Protein Transport
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Residues
/ Science
/ Science (multidisciplinary)
/ Substrates
/ Vector-borne diseases
/ Xenopus laevis
2020
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The natural function of the malaria parasite’s chloroquine resistance transporter
Journal Article
The natural function of the malaria parasite’s chloroquine resistance transporter
2020
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Overview
The
Plasmodium falciparum
chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite’s digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT’s native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.
Plasmodium falciparum
chloroquine resistance transporter (PfCRT) mediates multidrug resistance, but its natural function remains unclear. Here, Shafik et al. show that PfCRT transports host-derived peptides of 4-11 residues but not other ions or metabolites, and that drug-resistance-conferring PfCRT mutants have reduced peptide transport.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14
/ 14/1
/ 14/63
/ 64
/ 64/114
/ 82/1
/ 82/58
/ 82/80
/ 9/10
/ Animals
/ Antimalarials - pharmacology
/ Biological Transport, Active
/ Cytosol
/ Female
/ Host-Parasite Interactions - genetics
/ Host-Parasite Interactions - physiology
/ Humanities and Social Sciences
/ Humans
/ Ions
/ Malaria
/ Malaria, Falciparum - drug therapy
/ Malaria, Falciparum - metabolism
/ Malaria, Falciparum - parasitology
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Mutant Proteins - metabolism
/ Mutation
/ Peptides
/ Plasmodium falciparum - drug effects
/ Plasmodium falciparum - genetics
/ Plasmodium falciparum - metabolism
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Residues
/ Science
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