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- PDB-9w01: Cryo-EM structure of LARS1:IARS1 complex -

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Basic information

Entry
Database: PDB / ID: 9w01
TitleCryo-EM structure of LARS1:IARS1 complex
Components
  • Isoleucine--tRNA ligase, cytoplasmic
  • Leucine--tRNA ligase, cytoplasmic
KeywordsTRANSLATION / Aminoacyl-tRNA synthetase / complex
Function / homology
Function and homology information


isoleucine-tRNA ligase / isoleucyl-tRNA aminoacylation / isoleucine-tRNA ligase activity / glutamine-tRNA ligase activity / glutaminyl-tRNA aminoacylation / Selenoamino acid metabolism / leucine-tRNA ligase / leucine-tRNA ligase activity / leucyl-tRNA aminoacylation / cellular response to leucine starvation ...isoleucine-tRNA ligase / isoleucyl-tRNA aminoacylation / isoleucine-tRNA ligase activity / glutamine-tRNA ligase activity / glutaminyl-tRNA aminoacylation / Selenoamino acid metabolism / leucine-tRNA ligase / leucine-tRNA ligase activity / leucyl-tRNA aminoacylation / cellular response to leucine starvation / Cytosolic tRNA aminoacylation / aminoacyl-tRNA synthetase multienzyme complex / tRNA aminoacylation for protein translation / cellular response to L-leucine / aminoacyl-tRNA deacylase activity / positive regulation of TORC1 signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / endomembrane system / cellular response to amino acid starvation / cellular response to amino acid stimulus / GTPase activator activity / osteoblast differentiation / GTPase binding / lysosome / tRNA binding / endoplasmic reticulum / extracellular exosome / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
: / Isoleucine--tRNA ligase, cytoplasmic, ubiquitin-like / : / : / Leucine--tRNA ligase, ubiquitin-like domain / Leucine--tRNA ligase, RagD-binding domain / Domain of unknown function (DUF5915) / Isoleucine-tRNA ligase, type 2 / Isoleucyl tRNA synthetase type 2, anticodon-binding domain / Leucyl-tRNA synthetase, class Ia, archaeal/eukaryotic cytosolic ...: / Isoleucine--tRNA ligase, cytoplasmic, ubiquitin-like / : / : / Leucine--tRNA ligase, ubiquitin-like domain / Leucine--tRNA ligase, RagD-binding domain / Domain of unknown function (DUF5915) / Isoleucine-tRNA ligase, type 2 / Isoleucyl tRNA synthetase type 2, anticodon-binding domain / Leucyl-tRNA synthetase, class Ia, archaeal/eukaryotic cytosolic / Isoleucine-tRNA ligase / Aminoacyl-tRNA synthetase, class Ia / tRNA synthetases class I (I, L, M and V) / Valyl/Leucyl/Isoleucyl-tRNA synthetase, editing domain / Methionyl/Valyl/Leucyl/Isoleucyl-tRNA synthetase, anticodon-binding / Anticodon-binding domain of tRNA ligase / Aminoacyl-tRNA synthetase, class Ia, anticodon-binding / Aminoacyl-tRNA synthetase, class I, conserved site / Aminoacyl-transfer RNA synthetases class-I signature. / Rossmann-like alpha/beta/alpha sandwich fold
Similarity search - Domain/homology
Isoleucine--tRNA ligase, cytoplasmic / Leucine--tRNA ligase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsKim, Y. / Kim, J.C. / Kim, D.W. / Kim, J. / Lee, J. / Kim, S. / Kang, J.Y. / Park, H.S.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)2023R1A2C1005945 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2026
Title: Cryo-EM structure of the LARS1:IARS1 complex reveals a nutrient-responsive switch controlling mTORC1 signaling.
Authors: Youjin Kim / Joo-Chan Kim / Do-Wook Kim / Jinwoo Kim / Jaehun Choi / Seo Young Park / Jimin Lee / Ina Yoon / Sunghoon Kim / Jin Young Kang / Hee-Sung Park /
Abstract: Aminoacyl-tRNA synthetases (ARSs) assemble into the multi-tRNA synthetase complex (MSC) to mediate noncanonical functions in cell signaling and stress responses. Among them, human cytosolic leucyl- ...Aminoacyl-tRNA synthetases (ARSs) assemble into the multi-tRNA synthetase complex (MSC) to mediate noncanonical functions in cell signaling and stress responses. Among them, human cytosolic leucyl-tRNA synthetase 1 (LARS1) plays a central role in sensing leucine and activating mTORC1, thereby linking nutrient availability to metabolic regulation. Despite recent progress, fundamental questions remain unresolved about the regulatory mechanisms governing LARS1's non-canonical functions, particularly its structural organization within the MSC. Here, we employ an integrated approach combining structural, biochemical, and cellular analyses to investigate the noncanonical roles of LARS1. The cryo-EM structure of the LARS1:isoleucyl-tRNA synthetase 1 (IARS1) complex reveals that LARS1 binds to IARS1, its anchoring partner in the MSC, via its UNE-L domain. Amino acid stimulation induces LARS1 phosphorylation at Ser1070, Ser1077, and Ser1082, which are located at the interface with IARS1. These modifications disrupt the interaction, promote LARS1 dissociation from the MSC, and enable mTORC1 activation. This study highlights phosphorylation as a conserved and critical molecular switch that orchestrates the non-canonical functions of MSC by dynamically modulating the assembly and activity of its components in response to external stimuli.
History
DepositionJul 23, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Leucine--tRNA ligase, cytoplasmic
B: Isoleucine--tRNA ligase, cytoplasmic


Theoretical massNumber of molelcules
Total (without water)279,3732
Polymers279,3732
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, Native heterodimeric complex showing extensive interface interactions, gel filtration, co-eluted in the same single fraction
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Leucine--tRNA ligase, cytoplasmic / Leucyl-tRNA synthetase / LeuRS / cLRS


Mass: 134649.875 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LARS1, KIAA1352, LARS / Production host: Escherichia coli (E. coli) / References: UniProt: Q9P2J5, leucine-tRNA ligase
#2: Protein Isoleucine--tRNA ligase, cytoplasmic / Isoleucyl-tRNA synthetase / IRS / IleRS


Mass: 144723.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The N-terminal GST tag was cleaved by TEV protease, leaving a single Gly residue.
Source: (gene. exp.) Homo sapiens (human) / Gene: IARS1, IARS / Production host: Escherichia coli (E. coli) / References: UniProt: P41252, isoleucine-tRNA ligase
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of Leucyl-tRNA synthetase 1 and Isoleucyl-tRNA synthetase
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 98.97 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8 / Details: 20 mM Tris-HCl pH 8.0, 150 mM NaCl, 1 mM DTT
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMTris(hydroxymethyl) aminomethane hydrochlorideTris-HCl1
31 mMdithiothreitolDTT1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 96000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.8 sec. / Electron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 7504

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC4.2particle selection
2cryoSPARC4.2image acquisition
4cryoSPARC4.2CTF correction
7UCSF Chimera1.11.12model fittingfit in map
8PHENIX1.18.2model fittingDock_in_map
10cryoSPARC4.2initial Euler assignmentAb initio reconstruction
11cryoSPARC4.2final Euler assignmentNon-uniform refinement
12cryoSPARC4.2classification
13cryoSPARC4.23D reconstructionNon-uniform refinement
14PHENIX1.18.2model refinementreal space refinement
15Coot0.8.9model refinementmanual adjustment
CTF correctionDetails: Correction was performed following Homogeneous refinement
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4690000
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 135800 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Details: Initial fitting with Chimera followed by optimization using Phenix dock_in_map
Atomic model building
ID 3D fitting-IDChain-IDSource nameType
11AAlphaFoldin silico model
21BAlphaFoldin silico model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 65.29 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00677705
ELECTRON MICROSCOPYf_angle_d0.887510454
ELECTRON MICROSCOPYf_chiral_restr0.05811134
ELECTRON MICROSCOPYf_plane_restr0.00851337
ELECTRON MICROSCOPYf_dihedral_angle_d5.60011014

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