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- EMDB-47100: Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, A... -

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Basic information

Entry
Database: EMDB / ID: EMD-47100
TitleHuman LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, AMP bound)
Map data
Sample
  • Complex: Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, AMP bound)
    • Protein or peptide: Lysine--tRNA ligase
    • RNA: tRNA-Lys3
  • Ligand: ADENOSINE MONOPHOSPHATE
  • Ligand: LYSINE
  • Ligand: SODIUM ION
KeywordsLysRS / aminoacylation / docked state / tRNA-Lys3 / TRANSLATION
Function / homology
Function and homology information


ATP:ADP adenylyltransferase activity / basophil activation involved in immune response / positive regulation of inflammatory response to antigenic stimulus / Mitochondrial tRNA aminoacylation / lysine-tRNA ligase / Selenoamino acid metabolism / lysine-tRNA ligase activity / lysyl-tRNA aminoacylation / diadenosine tetraphosphate biosynthetic process / Cytosolic tRNA aminoacylation ...ATP:ADP adenylyltransferase activity / basophil activation involved in immune response / positive regulation of inflammatory response to antigenic stimulus / Mitochondrial tRNA aminoacylation / lysine-tRNA ligase / Selenoamino acid metabolism / lysine-tRNA ligase activity / lysyl-tRNA aminoacylation / diadenosine tetraphosphate biosynthetic process / Cytosolic tRNA aminoacylation / aminoacyl-tRNA synthetase multienzyme complex / positive regulation of macrophage activation / tRNA processing / amino acid binding / response to X-ray / Transcriptional and post-translational regulation of MITF-M expression and activity / ERK1 and ERK2 cascade / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / tRNA binding / mitochondrial matrix / positive regulation of DNA-templated transcription / protein homodimerization activity / mitochondrion / extracellular space / nucleoplasm / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Bacterial/eukaryotic lysine-tRNA ligase, class II / Lysine-tRNA ligase, class II / Lysine-tRNA ligase, class II, N-terminal / Lysyl-tRNA synthetase, class II, C-terminal / Aminoacyl-tRNA synthetase, class II (D/K/N) / tRNA synthetases class II (D, K and N) / OB-fold nucleic acid binding domain, AA-tRNA synthetase-type / OB-fold nucleic acid binding domain / Aminoacyl-tRNA synthetase, class II / Aminoacyl-transfer RNA synthetases class-II family profile. ...Bacterial/eukaryotic lysine-tRNA ligase, class II / Lysine-tRNA ligase, class II / Lysine-tRNA ligase, class II, N-terminal / Lysyl-tRNA synthetase, class II, C-terminal / Aminoacyl-tRNA synthetase, class II (D/K/N) / tRNA synthetases class II (D, K and N) / OB-fold nucleic acid binding domain, AA-tRNA synthetase-type / OB-fold nucleic acid binding domain / Aminoacyl-tRNA synthetase, class II / Aminoacyl-transfer RNA synthetases class-II family profile. / Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) / Nucleic acid-binding, OB-fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsDevarkar SC / Xiong Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI157890-01A1 (R21 grant) United States
CitationJournal: Nucleic Acids Res / Year: 2025
Title: Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase.
Authors: Swapnil C Devarkar / Christina R Budding / Chathuri Pathirage / Arundhati Kavoor / Cassandra Herbert / Patrick A Limbach / Karin Musier-Forsyth / Yong Xiong /
Abstract: The average eukaryotic transfer ribonucleic acid (tRNA) contains 13 post-transcriptional modifications; however, their functional impact is largely unknown. Our understanding of the complex tRNA ...The average eukaryotic transfer ribonucleic acid (tRNA) contains 13 post-transcriptional modifications; however, their functional impact is largely unknown. Our understanding of the complex tRNA aminoacylation machinery in metazoans also remains limited. Herein, using a series of high-resolution cryo-electron microscopy (cryo-EM) structures, we provide the mechanistic basis for recognition and aminoacylation of fully modified cellular tRNALys3 by human lysyl-tRNA synthetase (h-LysRS). The tRNALys3 anticodon loop modifications S34 (mcm5s2U) and R37 (ms2t6A) play an integral role in recognition by h-LysRS. Modifications in the T-, variable-, and D-loops of tRNALys3 are critical for ordering the metazoan-specific N-terminal domain of LysRS. The two catalytic steps of tRNALys3 aminoacylation are structurally ordered; docking of the 3'-CCA end in the active site cannot proceed until the lysyl-adenylate intermediate is formed and the pyrophosphate byproduct is released. Association of the h-LysRS-tRNALys3 complex with a multi-tRNA synthetase complex-derived peptide shifts the equilibrium toward the 3'-CCA end "docked" conformation and allosterically increases h-LysRS catalytic efficiency. The insights presented here have broad implications for understanding the role of tRNA modifications in protein synthesis, the human aminoacylation machinery, and the growing catalog of metabolic and neurological diseases linked to it.
History
DepositionSep 20, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47100.png

Downloads & links

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Map

FileDownload / File: emd_47100.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.43317854 - 0.8942406
Average (Standard dev.)-0.00011063578 (±0.020965535)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_47100_half_map_1.map
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Half map: #1

Fileemd_47100_half_map_2.map
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Sample components

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Entire : Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, A...

EntireName: Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, AMP bound)
Components
  • Complex: Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, AMP bound)
    • Protein or peptide: Lysine--tRNA ligase
    • RNA: tRNA-Lys3
  • Ligand: ADENOSINE MONOPHOSPHATE
  • Ligand: LYSINE
  • Ligand: SODIUM ION

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Supramolecule #1: Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, A...

SupramoleculeName: Human LysRS bound to unmodified tRNA-Lys3 (3'-CCA Docked State, AMP bound)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Lysine--tRNA ligase

MacromoleculeName: Lysine--tRNA ligase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
EC number: Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.143953 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAAVQAAEVK VDGSEPKLSK NELKRRLKAE KKVAEKEAKQ KELSEKQLSQ ATAAATNHTT DNGVGPEEES VDPNQYYKIR SQAIHQLKV NGEDPYPHKF HVDISLTDFI QKYSHLQPGD HLTDITLKVA GRIHAKRASG GKLIFYDLRG EGVKLQVMAN S RNYKSEEE ...String:
MAAVQAAEVK VDGSEPKLSK NELKRRLKAE KKVAEKEAKQ KELSEKQLSQ ATAAATNHTT DNGVGPEEES VDPNQYYKIR SQAIHQLKV NGEDPYPHKF HVDISLTDFI QKYSHLQPGD HLTDITLKVA GRIHAKRASG GKLIFYDLRG EGVKLQVMAN S RNYKSEEE FIHINNKLRR GDIIGVQGNP GKTKKGELSI IPYEITLLSP CLHMLPHLHF GLKDKETRYR QRYLDLILND FV RQKFIIR SKIITYIRSF LDELGFLEIE TPMMNIIPGG AVAKPFITYH NELDMNLYMR IAPELYHKML VVGGIDRVYE IGR QFRNEG IDLTHNPEFT TCEFYMAYAD YHDLMEITEK MVSGMVKHIT GSYKVTYHPD GPEGQAYDVD FTPPFRRINM VEEL EKALG MKLPETNLFE TEETRKILDD ICVAKAVECP PPRTTARLLD KLVGEFLEVT CINPTFICDH PQIMSPLAKW HRSKE GLTE RFELFVMKKE ICNAYTELND PMRQRQLFEE QAKAKAAGDD EAMFIDENFC TALEYGLPPT AGWGMGIDRV AMFLTD SNN IKEVLLFPAM KPEDKKENVA TTDTLESTTV GTSV

UniProtKB: Lysine--tRNA ligase

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Macromolecule #2: tRNA-Lys3

MacromoleculeName: tRNA-Lys3 / type: rna / ID: 2 / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.44748 KDa
SequenceString:
GCCCGGAUAG CUCAGUCGGU AGAGCAUCAG ACUUUUAAUC UGAGGGUCCA GGGUUCAAGU CCCUGUUCGG GCGCCA

GENBANK: GENBANK: L10753.1

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Macromolecule #3: ADENOSINE MONOPHOSPHATE

MacromoleculeName: ADENOSINE MONOPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: AMP
Molecular weightTheoretical: 347.221 Da
Chemical component information

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM

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Macromolecule #4: LYSINE

MacromoleculeName: LYSINE / type: ligand / ID: 4 / Number of copies: 2 / Formula: LYS
Molecular weightTheoretical: 147.195 Da
Chemical component information

ChemComp-LYS:
LYSINE

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Macromolecule #5: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 5 / Number of copies: 1
Molecular weightTheoretical: 22.99 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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 302069
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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