[English] 日本語
EMN Papers
- Database of articles cited by 3DEM data entries -

+
Search query

Keywords
Author
Journal
IF

-
Structure paper

TitleStructure and drug resistance of the Plasmodium falciparum transporter PfCRT.
Journal, issue, pagesNature, Year 2019
Publish dateNov 27, 2019
AuthorsJonathan Kim / Yong Zi Tan / Kathryn J Wicht / Satchal K Erramilli / Satish K Dhingra / John Okombo / Jeremie Vendome / Laura M Hagenah / Sabrina I Giacometti / Audrey L Warren / Kamil Nosol / Paul D Roepe / Clinton S Potter / Bridget Carragher / Anthony A Kossiakoff / Matthias Quick / David A Fidock / Filippo Mancia /
PubMed AbstractThe emergence and spread of drug-resistant Plasmodium falciparum impedes global efforts to control and eliminate malaria. For decades, treatment of malaria has relied on chloroquine (CQ), a safe and ...The emergence and spread of drug-resistant Plasmodium falciparum impedes global efforts to control and eliminate malaria. For decades, treatment of malaria has relied on chloroquine (CQ), a safe and affordable 4-aminoquinoline that was highly effective against intra-erythrocytic asexual blood-stage parasites, until resistance arose in Southeast Asia and South America and spread worldwide. Clinical resistance to the chemically related current first-line combination drug piperaquine (PPQ) has now emerged regionally, reducing its efficacy. Resistance to CQ and PPQ has been associated with distinct sets of point mutations in the P. falciparum CQ-resistance transporter PfCRT, a 49-kDa member of the drug/metabolite transporter superfamily that traverses the membrane of the acidic digestive vacuole of the parasite. Here we present the structure, at 3.2 Å resolution, of the PfCRT isoform of CQ-resistant, PPQ-sensitive South American 7G8 parasites, using single-particle cryo-electron microscopy and antigen-binding fragment technology. Mutations that contribute to CQ and PPQ resistance localize primarily to moderately conserved sites on distinct helices that line a central negatively charged cavity, indicating that this cavity is the principal site of interaction with the positively charged CQ and PPQ. Binding and transport studies reveal that the 7G8 isoform binds both drugs with comparable affinities, and that these drugs are mutually competitive. The 7G8 isoform transports CQ in a membrane potential- and pH-dependent manner, consistent with an active efflux mechanism that drives CQ resistance, but does not transport PPQ. Functional studies on the newly emerging PfCRT F145I and C350R mutations, associated with decreased PPQ susceptibility in Asia and South America, respectively, reveal their ability to mediate PPQ transport in 7G8 variant proteins and to confer resistance in gene-edited parasites. Structural, functional and in silico analyses suggest that distinct mechanistic features mediate the resistance to CQ and PPQ in PfCRT variants. These data provide atomic-level insights into the molecular mechanism of this key mediator of antimalarial treatment failures.
External linksPubMed:31776516 / Publisher's page
KeywordsMEMBRANE PROTEIN / Transporter / drug resistance / digestive vacuole of malaria parasite / nanodisc
MethodsEM (single particle)
Resolution3.3 A
Structure data

EMDB-20806:
Single-Particle Cryo-EM Structure of Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) 7G8 Isoform

PDB-6ukj:
Single-Particle Cryo-EM Structure of Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) 7G8 Isoform

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

Source
  • Plasmodium falciparum 7G8 (eukaryote)
  • homo sapiens (human)
  • plasmodium falciparum (isolate 7g8) (eukaryote)

+
About EMN Papers

-
News

-
Jul 5, 2019. Downlodablable text data

Downlodablable text data

  • Some data of EM Navigator services can be downloaded as text file. Software such as Excel can load the data files.
    PageDataFormat
    EMN Searchsearch resultCSV, TSV, or JSON
    EMN statisticsdata tableCSV or TSV

Related info.: EMN Search / EMN Statistics

-
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force. (see PDBe EMDB page)
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.: Q: What is "EMD"? / ID/Accession-code notation in Yorodumi/EM Navigator

External links: EMDB at PDBe / Contact to PDBj

+
Feb 20, 2018. PDBj/BINDS workshop in Osaka University

PDBj/BINDS workshop in Osaka University

    +
    Oct 4, 2017. Three pioneers of this field were awarded Nobel Prize in Chemistry 2017

    Three pioneers of this field were awarded Nobel Prize in Chemistry 2017

    • Jacques Dubochet (University of Lausanne, Switzerland) is a pioneer of ice-embedding method of EM specimen (as known as cryo-EM), Most of 3DEM structures in EMDB and PDB are obtained using his method.
    • Joachim Frank (Columbia University, New York, USA) is a pioneer of single particle reconstruction, which is the most used reconstruction method for 3DEM structures in EMDB and EM entries in PDB. And also, he is a develper of Spider, which is one of the most famous software in this field, and is used for some EM Navigor data (e.g. map projection/slice images).
    • Richard Henderson (MRC Laboratory of Molecular Biology, Cambridge, UK) was determined the first biomolecule structure by EM. The first EM entry in PDB, PDB-1brd is determinedby him.

    External links: The 2017 Nobel Prize in Chemistry - Press Release

    +
    Jul 12, 2017. Major update of PDB

    Major update of PDB

    • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary. This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated. See below links for details.
    • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software). Now, EM Navigator and Yorodumi are based on the updated data.

    External links: wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

    Read more

    -
    EMN Papers

    Database of articles cited by 3DEM data entries

    • Database of articles cited by 3DEM data entries in EMDB and PDB
    • Using PubMed data

    Related info.: EMDB / PDB / Q: What is the data source of EM Navigator? / EM Navigator / Yorodumi Papers / Changes in new EM Navigator and Yorodumi

    Read more