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- PDB-21aa: Structure of Human Aspartate--tRNA ligase 3-154 with linker and F... -

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Basic information

Entry
Database: PDB / ID: 21aa
TitleStructure of Human Aspartate--tRNA ligase 3-154 with linker and FC : ATYR0101
ComponentsAspartate--tRNA ligase, cytoplasmic,linker+FC
KeywordsAPOPTOSIS / Fibrosis / t-RNA synthase / Myofibroblast
Function / homology
Function and homology information


aminoacylase activity / aspartate-tRNA ligase / aspartate-tRNA ligase activity / aspartyl-tRNA aminoacylation / Selenoamino acid metabolism / Cytosolic tRNA aminoacylation / aminoacyl-tRNA synthetase multienzyme complex / tRNA aminoacylation for protein translation / Transcriptional and post-translational regulation of MITF-M expression and activity / protein-containing complex assembly ...aminoacylase activity / aspartate-tRNA ligase / aspartate-tRNA ligase activity / aspartyl-tRNA aminoacylation / Selenoamino acid metabolism / Cytosolic tRNA aminoacylation / aminoacyl-tRNA synthetase multienzyme complex / tRNA aminoacylation for protein translation / Transcriptional and post-translational regulation of MITF-M expression and activity / protein-containing complex assembly / translation / synapse / RNA binding / extracellular exosome / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
Aspartate-tRNA synthetase, type 2 / Aspartyl/Asparaginyl-tRNA synthetase, class IIb / 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
Aspartate--tRNA ligase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.96 Å
AuthorsNangle, L. / Tian, H. / Fung, C.P.
Funding support Hong Kong, 1items
OrganizationGrant numberCountry
Other government Hong Kong
CitationJournal: J Biol Chem / Year: 2026
Title: Natural Asp-tRNA Synthetase Fragment Targets Myofibroblasts to Abrogate Tissue Fibrosis.
Authors: Ryan A Adams / Ying-Ting Wang / Alison G Barber / Kristina Hamel / Andrew Imfeld / Luke Burman / Kaitlyn Rauch / Yeeting E Chong / Angelica Villanueva / Lauren Guy / Wayne Liu / Crystal ...Authors: Ryan A Adams / Ying-Ting Wang / Alison G Barber / Kristina Hamel / Andrew Imfeld / Luke Burman / Kaitlyn Rauch / Yeeting E Chong / Angelica Villanueva / Lauren Guy / Wayne Liu / Crystal Manzo / Sofia Klopp-Savino / Clara Polizzi / Jasmine Stamps / Max Pastenes / Honglei Tian / Chun Po Fung / Yingyi Zhang / Kwok Wa Hugo Ho / Bruno Sangiorgi / Blythe Dillingham / Tarsis F Brust / Kyle P Chiang / Zhenguo Wu / Zhiwen Xu / Christoph Burkart / Leslie A Nangle /
Abstract: Fibrosis remains a major global health challenge with limited therapies that only slow disease progression. While the aminoacyl-tRNA synthetase (aaRS) family is known to utilize evolutionarily ...Fibrosis remains a major global health challenge with limited therapies that only slow disease progression. While the aminoacyl-tRNA synthetase (aaRS) family is known to utilize evolutionarily appended domains as extracellular signaling molecules, their role in regulating the homeostasis of the fibrotic process is poorly defined. We identify a natural proteolytic fragment of aspartyl-tRNA synthetase (DARS), termed DARS-N1, that selectively triggers apoptosis in myofibroblasts by targeting latent-transforming growth factor beta binding protein 1 (LTBP-1) on the extracellular matrix (ECM). This active N-terminal fragment of DARS reduces focal adhesion kinase (FAK) activation in undifferentiated fibroblasts and myofibroblasts, while only myofibroblasts exhibit inadequate cell-matrix attachment leading to loss of anchorage-dependent survival and promotion of apoptosis. We utilized ATYR0101, a therapeutic form of DARS-N1 engineered for extended serum exposure, to demonstrate anti-fibrotic activity in lung (bleomycin). Spatial transcriptomics analysis showed that ATYR0101 activates a restorative program promoting the return to a healthy state. These findings highlight ATYR0101's potential as a transformative therapy for disrupting the process of chronic tissue fibrosis.
History
DepositionDec 4, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 14, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aspartate--tRNA ligase, cytoplasmic,linker+FC
B: Aspartate--tRNA ligase, cytoplasmic,linker+FC


Theoretical massNumber of molelcules
Total (without water)91,0552
Polymers91,0552
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Aspartate--tRNA ligase, cytoplasmic,linker+FC / Aspartyl-tRNA synthetase / AspRS / Cell proliferation-inducing gene 40 protein


Mass: 45527.676 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: N-terminal portion is flexible random loop and not visible in structure,N-terminal portion is flexible random loop and not visible in structure
Source: (gene. exp.) Homo sapiens (human) / Gene: DARS1, DARS, PIG40 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: P14868, aspartate-tRNA ligase
Has protein modificationY

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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: Human Aspartate--tRNA ligase 3-154: -Linker-Fcv14 / Type: COMPLEX
Details: Recombinant protein of N-terminal of Human Aspartate tRNA ligase and IgG FC
Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31synthetic construct (others)32630
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293F
Buffer solutionpH: 7.4 / Details: 1x PBS 7.4
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample is purified from Expi293F expression
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291.15 K
Details: To prepare cryo-grids, 3 ul samples were applied to glow discharged Quantifoil Cu grids (R1.2/1.3), which were subsequently blotted with filter paper (Ted Pella) for 3 seconds at 18oC and ...Details: To prepare cryo-grids, 3 ul samples were applied to glow discharged Quantifoil Cu grids (R1.2/1.3), which were subsequently blotted with filter paper (Ted Pella) for 3 seconds at 18oC and 100% humidity. The grids were immediately plunge frozen in liquid ethane using a FEI Vitrobot IV (ThermoFisher)

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k) / Num. of real images: 1414
Details: A total of 1,508 movies were acquired and imported into Cryo-SPARC using the following parameters: Raw pixel size 1.06 A, Accelerating Voltage 300 kV, Spherical Aberration 2.7 mm, and Total ...Details: A total of 1,508 movies were acquired and imported into Cryo-SPARC using the following parameters: Raw pixel size 1.06 A, Accelerating Voltage 300 kV, Spherical Aberration 2.7 mm, and Total exposure dose 50 e/A^2. Motion correction and CTF estimation were performed using Full-frame Motion Correction and Patch CTF. After that, 1,414 micrographs were selected from the 1,508 micrographs based on average intensity

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.7.0particle selection
2PHENIX"2.0_5885"model refinement
13cryoSPARC4.7.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionDetails: After Inspect Particle Picks (NCC score > 0.670, 10 < local power score < 59) and Extract From Micrographs (Extraction box size 200 pix), a total of 2,771,298 particles were extracted
3D reconstructionResolution: 4.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142250 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Details: Initial local fitting was done using Chimera X, followed by manual fitting using Coot. Finally it was refined using Phenix real space refinement
Atomic model buildingDetails: Intial model of st / Source name: AlphaFold / Type: in silico model
RefinementHighest resolution: 4.96 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0056294
ELECTRON MICROSCOPYf_angle_d0.6698590
ELECTRON MICROSCOPYf_dihedral_angle_d6.578844
ELECTRON MICROSCOPYf_chiral_restr0.049948
ELECTRON MICROSCOPYf_plane_restr0.0071136

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