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- EMDB-38557: Cryo-EM structure of Lassa virus RdRP elongation complex with the... -

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Basic information

Entry
Database: EMDB / ID: EMD-38557
TitleCryo-EM structure of Lassa virus RdRP elongation complex with the NTP form of compound HNC-1664 bound in the active site
Map data
Sample
  • Complex: Lassa virus RdRP elongation complex with the NTP form of compound 13b bound in the active site
    • Complex: Lassa virus L protein
      • Protein or peptide: RNA-directed RNA polymerase L
    • Complex: RNA
      • RNA: RNA (14-MER)
      • RNA: RNA (32-MER)
      • RNA: RNA (9-MER)
  • Ligand: [[(2~{R},3~{R},4~{S},5~{R})-4-fluoranyl-5-(5-iodanyl-4-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate
KeywordsLassa virus / RNA-dependent RNA polymerase / elongation complex / nucleoside analog / REPLICATION
Function / homology
Function and homology information


negative stranded viral RNA replication / cap snatching / virion component / host cell / Hydrolases; Acting on ester bonds / host cell cytoplasm / hydrolase activity / RNA-directed RNA polymerase / RNA-directed RNA polymerase activity / nucleotide binding / metal ion binding
Similarity search - Function
RNA polymerase, arenaviral / RNA endonuclease, cap-snatching / Arenavirus RNA polymerase / Arenavirus cap snatching domain / : / RNA-directed RNA polymerase, negative-strand RNA virus / RdRp of negative ssRNA viruses with segmented genomes catalytic domain profile.
Similarity search - Domain/homology
RNA-directed RNA polymerase L
Similarity search - Component
Biological speciesLassa virus Josiah / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsJing X / Gong P
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)(2022YFC2303300) China
National Natural Science Foundation of China (NSFC)U23A20147 China
CitationJournal: Nat Commun / Year: 2024
Title: An adenosine analog shows high antiviral potency against coronavirus and arenavirus mainly through an unusual base pairing mode.
Authors: Xiaoying Jia / Xuping Jing / Ming Li / Minli Gao / Yao Zhong / Entao Li / Yang Liu / Rui Li / Guoqiang Yao / Qiaojie Liu / Minmin Zhou / Yuxia Hou / Linfeng An / Yibao Hong / Shanshan Li / ...Authors: Xiaoying Jia / Xuping Jing / Ming Li / Minli Gao / Yao Zhong / Entao Li / Yang Liu / Rui Li / Guoqiang Yao / Qiaojie Liu / Minmin Zhou / Yuxia Hou / Linfeng An / Yibao Hong / Shanshan Li / Jiancun Zhang / Wei Wang / Kaiming Zhang / Peng Gong / Sandra Chiu /
Abstract: By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose- ...By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose-modified NAs do not present broad-spectrum features, likely due to differences in ribose-RdRP interactions across virus families. Here, we show that HNC-1664, an adenosine analog with modifications both in ribose and base, has broad-spectrum antiviral activity against positive-strand coronaviruses and negative-strand arenaviruses. Importantly, treatment with HNC-1664 demonstrate anti-SARS-CoV-2 efficacy in infected K18-human ACE2 mice, with reduced viral titer and mortality, as well as improved lung injury. Enzymology data demonstrate that HNC-1664 inhibits RNA synthesis mainly at the pre-catalysis stage. The cryo-EM structures of HNC-1664-bound RdRP-RNA complexes from both SARS-CoV-2 and LASV reveal an unusual base pairing mode of HNC-1664 in part due to its base modification, thus revealing its great potency in binding but not catalysis. Under certain circumstances, 1664-TP can be slowly incorporated by RdRP through regular Watson-Crick base pairing, as evidenced by enzymology data and an HNC-1664-incorporated crystal structure of the RdRP-RNA complex. Overall, HNC-1664 achieves broad-spectrum characteristics by favoring an alternative base pairing strategy to non-catalytically block RNA synthesis, providing a novel concept for the rational development of NA drugs.
History
DepositionJan 4, 2024-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38557.png

Downloads & links

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Map

FileDownload / File: emd_38557.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 256 pix.
= 243.2 Å		0.95 Å/pix.
x 256 pix.
= 243.2 Å		0.95 Å/pix.
x 256 pix.
= 243.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.95 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-1.0316502 - 1.7142092
Average (Standard dev.)0.0010359343 (±0.049127474)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 243.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_38557_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_38557_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_38557_half_map_2.map
Projections & Slices
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Sample components

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Entire : Lassa virus RdRP elongation complex with the NTP form of compound...

EntireName: Lassa virus RdRP elongation complex with the NTP form of compound 13b bound in the active site
Components
  • Complex: Lassa virus RdRP elongation complex with the NTP form of compound 13b bound in the active site
    • Complex: Lassa virus L protein
      • Protein or peptide: RNA-directed RNA polymerase L
    • Complex: RNA
      • RNA: RNA (14-MER)
      • RNA: RNA (32-MER)
      • RNA: RNA (9-MER)
  • Ligand: [[(2~{R},3~{R},4~{S},5~{R})-4-fluoranyl-5-(5-iodanyl-4-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate

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Supramolecule #1: Lassa virus RdRP elongation complex with the NTP form of compound...

SupramoleculeName: Lassa virus RdRP elongation complex with the NTP form of compound 13b bound in the active site
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Molecular weightTheoretical: 270 KDa

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Supramolecule #2: Lassa virus L protein

SupramoleculeName: Lassa virus L protein / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Lassa virus Josiah

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Supramolecule #3: RNA

SupramoleculeName: RNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#4
Source (natural)Organism: synthetic construct (others) / Synthetically produced: Yes

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Macromolecule #1: RNA-directed RNA polymerase L

MacromoleculeName: RNA-directed RNA polymerase L / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: RNA-directed RNA polymerase
Source (natural)Organism: Lassa virus Josiah
Molecular weightTheoretical: 255.200422 KDa
Recombinant expressionOrganism: Pichia (fungus)
SequenceString: MEEDIAYVKD LVSKYLVDNE RLSRQKLAFL VQTEPRMLLM EGLKLLSLCI EVDSCNANGC EHNSEDKSVE KILHECGILT PSLCFVVPD GYKLTGNVLI LLECFVRSSP ANFEQKYIED LKKLEQLRED LKSVDINLIP LIDGRTSFYN EQLPDWVNDK L RDTLFSLL ...String:
MEEDIAYVKD LVSKYLVDNE RLSRQKLAFL VQTEPRMLLM EGLKLLSLCI EVDSCNANGC EHNSEDKSVE KILHECGILT PSLCFVVPD GYKLTGNVLI LLECFVRSSP ANFEQKYIED LKKLEQLRED LKSVDINLIP LIDGRTSFYN EQLPDWVNDK L RDTLFSLL RYAQESNSLF EESEYSRLCE SLSMTSGRLS GIESLNTLLD NRSDHYEEII ALCHQGINNK LTAHEVKLQI EE EYQVFRN RLRGGEIKCQ FMRVNKDHLL SEFNKLYIDD GVVVEENLEQ LTHQFKRASP ILRFLYSDIE GEEDRRNTQA IKE HQMQCW RSFLNKVKSL RILNTRRKLL LIFDTLILLA SKYDHIKQGC LQGWLGSCFV SVNDRLVSLD STKRDLKKWI ERRQ QVESS KSTAPSQCLS KNQILSSIIQ KTIKRATAAM EDVGINMNHF GVDMSVIGLD CYDSIMNFDV TGVTPTISYQ KSQEE TFPY AMGVVELSET TDLGRLSSLS LALINSMKTS STVKLRQNEF GAARYQVVRC KEAYCQEFLL DGVKFQLVYQ KTGECS KCY AINNDKVGEV CSFYADPKRY FPAIFSAEVL QATVDTMITW IKDCNELEKE LTHIKLLTKM ILVLILAHPS KRSQKLL QN LRYFIMAYVS DYHHVDLMDK IKEKLITETE FLLYKLIRAL ISLILCNEVK SMMTNRFKFI LNVSYMCHFI TKETPDRL T DQIKCFEKFL EPKIEFGHVS VNPADIATEE ELMDMAYHAK KFLSKEGCTA PRGPEYKKPG VSKKFLSLLT SSFNNGSLF KEKEVKKELR DPIITSGCAT ALDLASNKSV VVNKYTDGSR VLNYDFNKLT ALAVTQLTEV FSRKGKHLLN RQDYEYKVQQ AMSNLVLGS QQQGVNVDRS DLDEILLEGS ASLYFDQLRE TVQKIVDQYR EPAGLGSMKG GNSEPSINDL DELIPNKFHI R LIKGELSN HMVEDFDCEI LPDSFYKEFC DNVYSNHKMK EKYFYCGHMS QCPIGELSKA VTTRTYFEQE YFQCFKSVLL IM NANKLMG KYSHYRSRNL NFKFDTGKLS DDVRISERES NSEALSKALS LTNCTTAMLK NLCFYSQESP QSYNSVGPDT GRL KFSLSY KEQVGGNREL YIGDLRTKMF TRLIEDYFEA LSLQLSGSCL NNEKEFENAI LSMKLNVSLA HVSYSMDHSK WGPM MCPFL FLAVLQNLIF LSKDLQADIK GRDYLSTLLT WHMHKMVEIP FNVVSAMMKS FIKAQLGLRK STSQSITEDF FYSNF QVGV VPSHVSSILD MGQGILHNTS DFYALISERF INYAISSVCG GSIDAYTSSD DQISLFNQDL TDLMQRDPEE FKTLLE FHY YMSNQLNKFI SPKSVVGRFV AEFKSRFYVW GDEVPLLTKF VAAALHNIKC KEPHQLAETI DTIIDQSVAN GVPVHLC NL IQLRTLSLLQ YARYPIDPFL LNCETDVKDW VDGNRSYRIM RQIESLIPEA CGKIRSMLRK LFNKLKTGQL HEEFTTNY L SGEHVSSLKN LCIILDVDPP SESDLEFSWL NLAAYHPLRM VLRQKVIYSG AVNLDDEKIP TIVKTIQNKL SSTFTRGAQ KLLSEAINKS AFQSSIASGF VGLCRTLGSK CVRGPNKENL YIKSIQSLIS NTQGIELLTN NHGIQYWRVP LNLKEEKISV AGYFRPLLW DYMCISLSTA IELGAWVLGE PKAAKPLEFF KHNPCDYFPL KPTASKLLED RVGVNHIIHS LRRLYPSMFE K HILPFMSD LASTKMKWSP RIKFLDLCVA LDVNCEALSL VSHIVKWKRE EHYIVLSSEL RLSHSRSHEP MVEERVVSTS DA VDNFMRQ IYFESYVRSF VATTRTLGSF TWFPHKTSIP EGEGLQRLGP FSSFVEKVIY KGIERPMFKY DLMMGYAWID FDV EPAKFN YNQLIASGLV SSKFDSLEDF FDAIESLPPG SVKLSQTIRF QIKSQDASFR ESFAIHLNFV GSMNEQGKYL VQDV AVMYS GAVNSCVLTD CWRLVLSGPT FKGKSAWYVD TEAINEFMSD TNQLGEVTPV EIVIDIDRLQ FVEHDFVLVG PCSEA IPLV VHRGGLWECN KRLASFSPVL QDQDLELFVR EVGDTSPDLL IGALSAMMLD RLKLRMQWSG VDIVSVLKKV MPKDGL KVL NAAFEAVDDW IEFKGYALCF SKSKRRVMIQ SSGGKLRLKG RTCEELLEKE EEVEDIESAS NSLEVLFQ

UniProtKB: RNA-directed RNA polymerase L

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Macromolecule #2: RNA (14-MER)

MacromoleculeName: RNA (14-MER) / type: rna / ID: 2 / Number of copies: 1
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 4.516763 KDa
SequenceString:
GCGCACCGGG GAUC

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Macromolecule #3: RNA (32-MER)

MacromoleculeName: RNA (32-MER) / type: rna / ID: 3 / Number of copies: 1
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 10.374283 KDa
SequenceString:
GGGAGAUGAA AGUCUCCAAC UGAAGAGUCC AA

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Macromolecule #4: RNA (9-MER)

MacromoleculeName: RNA (9-MER) / type: rna / ID: 4 / Number of copies: 1
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 2.808703 KDa
SequenceString:
GGACUCUUC

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Macromolecule #5: [[(2~{R},3~{R},4~{S},5~{R})-4-fluoranyl-5-(5-iodanyl-4-methyl-pyr...

MacromoleculeName: [[(2~{R},3~{R},4~{S},5~{R})-4-fluoranyl-5-(5-iodanyl-4-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1LVZ
Molecular weightTheoretical: 633.092 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 225955
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8xpo:
Cryo-EM structure of Lassa virus RdRP elongation complex with the NTP form of compound HNC-1664 bound in the active site

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