- EMDB-8576: Structure of the Plasmodium falciparum 80S ribosome bound to the ... -
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Basic information
Entry
Database: EMDB / ID: EMD-8576
Title
Structure of the Plasmodium falciparum 80S ribosome bound to the antimalarial drug mefloquine
Map data
Sample
Complex: Plasmodium falciparum 80S ribosome bound to mefloquine
RNA: x 3 types
Protein or peptide: x 42 types
Ligand: x 3 types
Keywords
Ribosome / protein synthesis / antimalarial
Function / homology
Function and homology information
Translesion synthesis by REV1 / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Translesion synthesis by POLK / Translesion synthesis by POLI / Josephin domain DUBs / Metalloprotease DUBs / DNA Damage Recognition in GG-NER / Formation of Incision Complex in GG-NER / Dual Incision in GG-NER ...Translesion synthesis by REV1 / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Translesion synthesis by POLK / Translesion synthesis by POLI / Josephin domain DUBs / Metalloprotease DUBs / DNA Damage Recognition in GG-NER / Formation of Incision Complex in GG-NER / Dual Incision in GG-NER / Formation of TC-NER Pre-Incision Complex / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / ER Quality Control Compartment (ERQC) / Iron uptake and transport / L13a-mediated translational silencing of Ceruloplasmin expression / SRP-dependent cotranslational protein targeting to membrane / Translation initiation complex formation / Formation of a pool of free 40S subunits / Formation of the ternary complex, and subsequently, the 43S complex / Ribosomal scanning and start codon recognition / GTP hydrolysis and joining of the 60S ribosomal subunit / Negative regulators of DDX58/IFIH1 signaling / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Aggrephagy / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases / Neddylation / MAPK6/MAPK4 signaling / Antigen processing: Ubiquitination & Proteasome degradation / ABC-family proteins mediated transport / AUF1 (hnRNP D0) binds and destabilizes mRNA / protein-RNA complex assembly / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / maturation of LSU-rRNA / ribosomal large subunit biogenesis / ribosomal large subunit assembly / modification-dependent protein catabolic process / large ribosomal subunit / protein tag activity / ribosome biogenesis / 5S rRNA binding / large ribosomal subunit rRNA binding / ubiquitin-dependent protein catabolic process / cytosolic small ribosomal subunit / cytosolic large ribosomal subunit / cytoplasmic translation / rRNA binding / negative regulation of translation / ribosome / protein ubiquitination / structural constituent of ribosome / ribonucleoprotein complex / translation / mRNA binding / ubiquitin protein ligase binding / RNA binding / nucleus / metal ion binding / cytoplasm Similarity search - Function
Ribosomal L28e/Mak16 / Ribosomal L28e protein family / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein L29e / Ribosomal L29e protein family / Ribosomal protein L13e, conserved site / Ribosomal protein L13e signature. / Ribosomal protein L22e / Ribosomal protein L22e superfamily ...Ribosomal L28e/Mak16 / Ribosomal L28e protein family / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein L29e / Ribosomal L29e protein family / Ribosomal protein L13e, conserved site / Ribosomal protein L13e signature. / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / Ribosomal protein L44e signature. / Ribosomal protein L10e, conserved site / Ribosomal protein L10e signature. / Ribosomal protein L10e / Ribosomal protein L13e / Ribosomal protein L13e / Ribosomal protein L19, eukaryotic / 60S ribosomal protein L18a/ L20, eukaryotes / Ribosomal protein L44e / Ribosomal protein L44 / Ribosomal protein L34e, conserved site / Ribosomal protein L34e signature. / Ribosomal protein L5 eukaryotic, C-terminal / Ribosomal L18 C-terminal region / 50S ribosomal protein L18Ae/60S ribosomal protein L20 and L18a / Ribosomal L40e family / Ribosomal protein L30e signature 1. / Ribosomal protein 50S-L18Ae/60S-L20/60S-L18A / Ribosomal proteins 50S-L18Ae/60S-L20/60S-L18A / Ribosomal_L40e / Ribosomal protein L40e / Ribosomal protein L40e superfamily / Eukaryotic Ribosomal Protein L27, KOW domain / Ribosomal protein L23/L25, N-terminal / Ribosomal protein L23, N-terminal domain / Ribosomal protein L30e signature 2. / Ribosomal protein L30e, conserved site / Ribosomal protein 60S L18 and 50S L18e / Ribosomal protein L27e / Ribosomal protein L27e superfamily / Ribosomal L27e protein family / Ribosomal protein L36e signature. / Ribosomal protein L39e, conserved site / Ribosomal protein L39e signature. / Ribosomal protein L34Ae / Ribosomal protein L34e / 60S ribosomal protein L19 / Ribosomal protein L18/L18-A/B/e, conserved site / Ribosomal protein L18e signature. / Ribosomal protein L30/YlxQ / 60S ribosomal protein L35 / Ribosomal protein L13, eukaryotic/archaeal / Ribosomal protein L7A/L8 / Ribosomal protein L6e / 60S ribosomal protein L6E / Ribosomal protein L18e / 60S ribosomal protein L4, C-terminal domain / 60S ribosomal protein L4 C-terminal domain / Ribosomal protein L37ae / Ribosomal protein L7, eukaryotic / Ribosomal protein L31e, conserved site / Ribosomal L37ae protein family / Ribosomal protein L31e signature. / Ribosomal_L19e / Ribosomal protein L30, N-terminal / Ribosomal L30 N-terminal domain / Ribosomal protein L19/L19e / Ribosomal protein L19/L19e, domain 1 / Ribosomal protein L19/L19e superfamily / Ribosomal protein L19e / Ribosomal protein L36e / Ribosomal protein L36e domain superfamily / Ribosomal protein L36e / Ribosomal protein L39e / Ribosomal protein L14e domain / Ribosomal protein L39e domain superfamily / Ribosomal L39 protein / Ribosomal protein L14 / Ribosomal protein L5 eukaryotic/L18 archaeal / Ribosomal large subunit proteins 60S L5, and 50S L18 / Ribosomal protein L35A / Ribosomal protein L35Ae / Ribosomal protein L35A superfamily / Ribosomal protein L32e, conserved site / Ribosomal protein L32e signature. / Ribosomal protein L14 / Ribosomal protein L14, KOW motif / Ribosomal protein L31e / Ribosomal protein L15e, conserved site / Ribosomal protein L31e domain superfamily / Ribosomal protein L31e / Ribosomal protein L15e signature. / Ribosomal_L31e / Ribosomal protein L21e / Ribosomal protein L21e, conserved site / Ribosomal protein L21 superfamily Similarity search - Domain/homology
Ribosomal protein L15 / 60S ribosomal protein L39 / Ribosomal protein L37 / 60S ribosomal protein L18-2, putative / 60S ribosomal protein L19 / 60S ribosomal protein L27a, putative / 60S ribosomal protein L41 / 60S ribosomal protein L29 / 60S ribosomal protein L26, putative / Large ribosomal subunit protein eL43 ...Ribosomal protein L15 / 60S ribosomal protein L39 / Ribosomal protein L37 / 60S ribosomal protein L18-2, putative / 60S ribosomal protein L19 / 60S ribosomal protein L27a, putative / 60S ribosomal protein L41 / 60S ribosomal protein L29 / 60S ribosomal protein L26, putative / Large ribosomal subunit protein eL43 / Large ribosomal subunit protein eL42 / 60S ribosomal protein L7, putative / 60S ribosomal protein L32 / 60S ribosomal protein L2 / 60S ribosomal protein L4 / 60S ribosomal protein L31 / 60S ribosomal protein L36 / 60S ribosomal protein L13 / Large ribosomal subunit protein eL22 / 60S ribosomal protein L11a, putative / 60S ribosomal protein L34 / Ubiquitin-60S ribosomal protein L40 / 60S ribosomal protein L17, putative / 60S ribosomal protein L18a / 60S ribosomal protein L6-2, putative / 60S ribosomal protein L23, putative / 60S ribosomal protein L23 / 60S ribosomal protein L6, putative / 60S ribosomal protein L24, putative / 60S ribosomal protein L35ae, putative / 60S ribosomal protein L28 / 60S ribosomal protein L38 / 60S ribosomal protein L35, putative / 60S ribosomal protein L3 / 60S ribosomal protein L30e, putative / 60S ribosomal protein L13, putative / 60S ribosomal protein L27 / 60S ribosomal protein L14, putative / 60S ribosomal protein L21 / 60S ribosomal protein L7a / 60S ribosomal protein L5, putative / 60S ribosomal protein L10, putative Similarity search - Component
Biological species
Plasmodium falciparum 3D7 (eukaryote)
Method
single particle reconstruction / cryo EM / Resolution: 3.2 Å
Department of Industry, Innovation, Science, Research and Tertiary Education, Australian Government|Australian Research Council
FT100100112
Australia
Citation
Journal: Nat Microbiol / Year: 2017 Title: Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis. Authors: Wilson Wong / Xiao-Chen Bai / Brad E Sleebs / Tony Triglia / Alan Brown / Jennifer K Thompson / Katherine E Jackson / Eric Hanssen / Danushka S Marapana / Israel S Fernandez / Stuart A Ralph ...Authors: Wilson Wong / Xiao-Chen Bai / Brad E Sleebs / Tony Triglia / Alan Brown / Jennifer K Thompson / Katherine E Jackson / Eric Hanssen / Danushka S Marapana / Israel S Fernandez / Stuart A Ralph / Alan F Cowman / Sjors H W Scheres / Jake Baum / Abstract: Malaria control is heavily dependent on chemotherapeutic agents for disease prevention and drug treatment. Defining the mechanism of action for licensed drugs, for which no target is characterized, ...Malaria control is heavily dependent on chemotherapeutic agents for disease prevention and drug treatment. Defining the mechanism of action for licensed drugs, for which no target is characterized, is critical to the development of their second-generation derivatives to improve drug potency towards inhibition of their molecular targets. Mefloquine is a widely used antimalarial without a known mode of action. Here, we demonstrate that mefloquine is a protein synthesis inhibitor. We solved a 3.2 Å cryo-electron microscopy structure of the Plasmodium falciparum 80S ribosome with the (+)-mefloquine enantiomer bound to the ribosome GTPase-associated centre. Mutagenesis of mefloquine-binding residues generates parasites with increased resistance, confirming the parasite-killing mechanism. Furthermore, structure-guided derivatives with an altered piperidine group, predicted to improve binding, show enhanced parasiticidal effect. These data reveal one possible mode of action for mefloquine and demonstrate the vast potential of cryo-electron microscopy to guide the development of mefloquine derivatives to inhibit parasite protein synthesis.
History
Deposition
Jan 27, 2017
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Header (metadata) release
Mar 1, 2017
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Map release
Mar 1, 2017
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Update
May 15, 2024
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Current status
May 15, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Name: MAGNESIUM ION / type: ligand / ID: 47 / Number of copies: 164 / Formula: MG
Molecular weight
Theoretical: 24.305 Da
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Macromolecule #48: ZINC ION
Macromolecule
Name: ZINC ION / type: ligand / ID: 48 / Number of copies: 5 / Formula: ZN
Molecular weight
Theoretical: 65.409 Da
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Experimental details
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Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Buffer
pH: 7.4 Details: 20 mM Hepes pH 7.4, 40 mM KAc, 10 mM NH4Ac, 10 mM Mg(Ac)2 and 5 mM 2-mecaptoethanol
Grid
Model: Quantifoil R2/2 / Material: COPPER / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 0.02 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Details: Blot 2.5s before plunging
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 90 K / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
FEI POLARA 300
Temperature
Min: 80.0 K / Max: 90.0 K
Image recording
Film or detector model: FEI FALCON II (4k x 4k) / Number grids imaged: 1 / Average electron dose: 20.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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