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- EMDB-52957: Structure of Cystathionine gamma-lyase -

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Basic information

Entry
Database: EMDB / ID: EMD-52957
TitleStructure of Cystathionine gamma-lyase
Map data
Sample
  • Organelle or cellular component: Cystathionine gamma-lyase
Keywordsenzyme / four fold symmetry / CYTOSOLIC PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.06 Å
AuthorsUchikawa E / Nasi S / So A / Driss A
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
Innosuisse56394.1 IP-LSEuropean Union
CitationJournal: Pharmacol Res / Year: 2025
Title: Allosteric activators of cystathionine γ lyase to augment endogenous hydrogen sulfide and inhibit pathologic calcification.
Authors: Sonia Nasi / Driss Ehirchiou / Cindy Blatter / Veronique Chobaz / Stefan Germann / Alexandra Brandenberger / Elias Bommeli / Emiko Uchikawa / Giuseppe Cirino / Rainer Riedl / Alexander So / Nathalie Busso /
Abstract: Hydrogen sulfide (H₂S), a gasotransmitter naturally produced in the body by enzymes such as cystathionine γ lyase (CSE), helps reduce inflammation, oxidative stress, and abnormal tissue ...Hydrogen sulfide (H₂S), a gasotransmitter naturally produced in the body by enzymes such as cystathionine γ lyase (CSE), helps reduce inflammation, oxidative stress, and abnormal tissue calcification. We present a novel strategy to boost endogenous H₂S production via CSE allosteric activation. Two CSE positive allosteric modulators (CSE-PAMs) were identified. Despite moderate binding affinity, both compounds induced a strong allosteric effect, increasing H₂S production by approximately 200 %. Cryo-electron microscopy and proteomics identified a distinct allosteric binding pocket on recombinant human CSE. In cellular assays, both compounds elevated H₂S levels. This correlated with inhibition of calcification. In chondrocytes, CSE-PAMs reduced alkaline phosphatase activity, inflammatory cytokine secretion, and oxidative stress, while enhancing protein persulfidation. These results highlight CSE-PAMs as promising therapeutic agents for conditions involving pathological calcification and inflammation, such as osteoarthritis. Additionally, they serve as valuable tools for investigating CSE-derived H₂S biology, previously limited by a lack of specific modulators.
History
DepositionFeb 26, 2025-
Header (metadata) releaseSep 10, 2025-
Map releaseSep 10, 2025-
UpdateSep 10, 2025-
Current statusSep 10, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52957.png

Downloads & links

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Map

FileDownload / File: emd_52957.map.gz / Format: CCP4 / Size: 290.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 424 pix.
= 307.824 Å		0.73 Å/pix.
x 424 pix.
= 307.824 Å		0.73 Å/pix.
x 424 pix.
= 307.824 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.726 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.003
Minimum - Maximum-0.0048863073 - 0.011517733
Average (Standard dev.)0.000003098773 (±0.0001784319)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions424424424
Spacing424424424
CellA=B=C: 307.824 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52957_msk_1.map
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Additional map: #1

Fileemd_52957_additional_1.map
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Half map: #2

Fileemd_52957_half_map_1.map
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Half map: #1

Fileemd_52957_half_map_2.map
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Sample components

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Entire : Cystathionine gamma-lyase

EntireName: Cystathionine gamma-lyase
Components
  • Organelle or cellular component: Cystathionine gamma-lyase

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Supramolecule #1: Cystathionine gamma-lyase

SupramoleculeName: Cystathionine gamma-lyase / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: tetramer
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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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: 7.4
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O4SHepes
150.0 mMNaClsodium chloride
1.0 mMC8H10NO6PPyridoxal phosphate
GridModel: SPT Labtech self-wicking R1.2/0.8 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Instrument: SPT LABTECH CHAMELEON

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 2875 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 150000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 321405
CTF correctionSoftware - Name: RELION (ver. 4.0.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.06 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 148058
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0.1)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 5.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

2nmp


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: AB INITIO MODEL

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