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A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance

Lakshmanan, V., Bray, Patrick, Verdier-Pinard, D., Johnson, David, Horrocks, P., Muhle, R. A., Alakpa, G. E., Hughes, Ruth, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192, Krogstad, D. J., Sidhu, A. B. S. and Fidock, D. A. (2005) 'A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance'. Embo Journal, Vol 24, Issue 13, pp. 2294-2305.

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Abstract

Chloroquine resistance (CQR) in Plasmodium falciparum is associated with mutations in the digestive vacuole transmembrane protein PfCRT. However, the contribution of individual pfcrt mutations has not been clarified and other genes have been postulated to play a substantial role. Using allelic exchange, we show that removal of the single PfCRT amino-acid change K76T from resistant strains leads to wild-type levels of CQ susceptibility, increased binding of CQ to its target ferriprotoporphyrin IX in the digestive vacuole and loss of verapamil reversibility of CQ and quinine resistance. Our data also indicate that PfCRT mutations preceding residue 76 modulate the degree of verapamil reversibility in CQ-resistant lines. The K76T mutation accounts for earlier observations that CQR can be overcome by subtly altering the CQ side-chain length. Together, these findings establish PfCRT K76T as a critical component of CQR and suggest that CQ access to ferriprotoporphyrin IX is determined by drug - protein interactions involving this mutant residue.

Item Type: Article
Additional Information: This article is freely available at the following URL: http://www.nature.com/emboj/journal/v24/n13/full/7600681a.html
Uncontrolled Keywords: chloroquine resistance drug accumulation ferriprotoporphyrin ix pfcrt verapamil drug/metabolite transporter superfamily malaria-infected erythrocytes transmembrane protein pfcrt drug-resistance digestive vacuole in-vitro mutations gene mechanism parasites
Subjects: QV Pharmacology > QV 38 Drug action.
QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified.
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1038/sj.emboj.7600681
Depositing User: Sarah Lewis-Newton
Date Deposited: 10 Oct 2011 15:33
Last Modified: 06 Feb 2018 13:02
URI: http://archive.lstmed.ac.uk/id/eprint/1882

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