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- EMDB-41732: Cryo-EM structure of bovine concentrative nucleoside transporter ... -
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Open data
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Basic information
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Title | Cryo-EM structure of bovine concentrative nucleoside transporter 3 in complex with GS-441524, consensus reconstruction | |||||||||
![]() | full map | |||||||||
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![]() | membrane protein / transporter / nucleoside / TRANSPORT PROTEIN | |||||||||
Function / homology | ![]() Ribavirin ADME / Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane / uridine transmembrane transporter activity / pyrimidine- and adenosine-specific:sodium symporter activity / purine-specific nucleoside:sodium symporter activity / pyrimidine nucleoside transport / Azathioprine ADME / purine nucleoside transmembrane transport / brush border membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.31 Å | |||||||||
![]() | Wright NJ / Lee S-Y | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Antiviral drug recognition and elevator-type transport motions of CNT3. Authors: Nicholas J Wright / Feng Zhang / Yang Suo / Lingyang Kong / Ying Yin / Justin G Fedor / Kedar Sharma / Mario J Borgnia / Wonpil Im / Seok-Yong Lee / ![]() Abstract: Nucleoside analogs have broad clinical utility as antiviral drugs. Key to their systemic distribution and cellular entry are human nucleoside transporters. Here, we establish that the human ...Nucleoside analogs have broad clinical utility as antiviral drugs. Key to their systemic distribution and cellular entry are human nucleoside transporters. Here, we establish that the human concentrative nucleoside transporter 3 (CNT3) interacts with antiviral drugs used in the treatment of coronavirus infections. We report high-resolution single-particle cryo-electron microscopy structures of bovine CNT3 complexed with antiviral nucleosides N-hydroxycytidine, PSI-6206, GS-441524 and ribavirin, all in inward-facing states. Notably, we found that the orally bioavailable antiviral molnupiravir arrests CNT3 in four distinct conformations, allowing us to capture cryo-electron microscopy structures of drug-loaded outward-facing and drug-loaded intermediate states. Our studies uncover the conformational trajectory of CNT3 during membrane transport of a nucleoside analog antiviral drug, yield new insights into the role of interactions between the transport and the scaffold domains in elevator-like domain movements during drug translocation, and provide insights into the design of nucleoside analog antiviral prodrugs with improved oral bioavailability. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19 KB 19 KB | Display Display | ![]() |
Images | ![]() | 83.7 KB | ||
Filedesc metadata | ![]() | 6.7 KB | ||
Others | ![]() ![]() | 59.5 MB 59.5 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8tz3MC ![]() 8tz1C ![]() 8tz2C ![]() 8tz4C ![]() 8tz5C ![]() 8tz6C ![]() 8tz7C ![]() 8tz8C ![]() 8tz9C ![]() 8tzaC ![]() 8tzdC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Map
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Annotation | full map | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: half map 1
File | emd_41732_half_map_1.map | ||||||||||||
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Annotation | half map 1 | ||||||||||||
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Density Histograms |
-Half map: half map 2
File | emd_41732_half_map_2.map | ||||||||||||
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Annotation | half map 2 | ||||||||||||
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Sample components
-Entire : bCNT3 trimer
Entire | Name: bCNT3 trimer |
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Components |
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-Supramolecule #1: bCNT3 trimer
Supramolecule | Name: bCNT3 trimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 232 KDa |
-Macromolecule #1: Sodium/nucleoside cotransporter
Macromolecule | Name: Sodium/nucleoside cotransporter / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 79.376773 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MDYKDDDDKL EATMAMSSKI SVELQRVAAL PAQGCSNTGF QNDEDGFENQ NPSGNDHSLR NRVVQNREHE NGKQVEEHIT IGQDSLRKD EEEEDDQETH RKGCLERMCG RMSDFCREHK TTLRYIIWGI LIAGYLALVI AACVMNFHRA LPLFVITVVA I FFVVWDHL ...String: MDYKDDDDKL EATMAMSSKI SVELQRVAAL PAQGCSNTGF QNDEDGFENQ NPSGNDHSLR NRVVQNREHE NGKQVEEHIT IGQDSLRKD EEEEDDQETH RKGCLERMCG RMSDFCREHK TTLRYIIWGI LIAGYLALVI AACVMNFHRA LPLFVITVVA I FFVVWDHL MAKYESQIAR FLSPGQRLLD SHWFWLKWVI WGCLILGVIL WLVFDTAKLG QQQLVSFGGL IIYTSLTFLF SK HPTKVYW RPVFWGIGLQ FLLGLLILRT EPGFMAFDWL GKQVQTFLGY SDAGASFVFG EKYTDHFFAF KVLPIVIFFS TVM SMLYYL GLMQWIIRKV GWVMLVTMGT SPVESVVASG NIFIGQTESP LLVRPYLPYV TKSELHAIMT AGFSTIAGSV LGAY ISFGV SSSHLLTASV MSAPAALAIS KLFWPETETP KINLKNAMKM ESGDSRNLLE AATQGASSSI SLVANIAVNL IAFLA LLSF MNSALSWLGN MFDYPQLSFE VICSYVFMPF AFMMGVDWQD SFMVAKLIGY KTFFNEFVAY QQLSKLISLR QVGGPK FVD GVQQYMSMRS EAISTYALCG FANFGSLGIV IGGLTSMAPS RKRDITAGAM RALIAGTIAC FLTACIAGML TNTPVDI NC HHILENAFNS GLVRNTTNVV SCCQGLLSSA VVKGPGEVIP TGNHSLYSLK NCCNLLNTPT LNCSWIPNVL SNS UniProtKB: Sodium/nucleoside cotransporter |
-Macromolecule #2: SODIUM ION
Macromolecule | Name: SODIUM ION / type: ligand / ID: 2 / Number of copies: 6 |
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Molecular weight | Theoretical: 22.99 Da |
-Macromolecule #3: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
Macromolecule | Name: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 3 / Number of copies: 12 / Formula: LBN |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-LBN: |
-Macromolecule #4: water
Macromolecule | Name: water / type: ligand / ID: 4 / Number of copies: 15 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 8 mg/mL | ||||||
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Buffer | pH: 8 / Component:
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: LEICA EM GP |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 12707 / Average exposure time: 2.4 sec. / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |