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- EMDB-52956: Structure of Cystathionine gamma-lyase with ZHAWOC24000 -

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Basic information

Entry
Database: EMDB / ID: EMD-52956
TitleStructure of Cystathionine gamma-lyase with ZHAWOC24000
Map data
Sample
  • Complex: Complex of Cystathionine gamma-lyase and ZHAWOC24000
    • Protein or peptide: Cystathionine gamma-lyase
Keywordsenzyme / four fold / CYTOSOLIC PROTEIN
Function / homology
Function and homology information


protein sulfhydration / selenocystathionine gamma-lyase activity / positive regulation of aortic smooth muscle cell differentiation / L-cystine L-cysteine-lyase (deaminating) / protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine / homocysteine desulfhydrase activity / homocysteine desulfhydrase / Cysteine formation from homocysteine / cystathionine gamma-lyase / Degradation of cysteine and homocysteine ...protein sulfhydration / selenocystathionine gamma-lyase activity / positive regulation of aortic smooth muscle cell differentiation / L-cystine L-cysteine-lyase (deaminating) / protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine / homocysteine desulfhydrase activity / homocysteine desulfhydrase / Cysteine formation from homocysteine / cystathionine gamma-lyase / Degradation of cysteine and homocysteine / cystathionine gamma-lyase activity / Metabolism of ingested SeMet, Sec, MeSec into H2Se / L-cysteine desulfhydrase activity / cysteine biosynthetic process via cystathionine / hydrogen sulfide biosynthetic process / cysteine biosynthetic process / cysteine metabolic process / transsulfuration / negative regulation of apoptotic signaling pathway / endoplasmic reticulum unfolded protein response / cellular response to leukemia inhibitory factor / lipid metabolic process / pyridoxal phosphate binding / protein homotetramerization / calmodulin binding / positive regulation of canonical NF-kappaB signal transduction / extracellular exosome / identical protein binding / cytosol / cytoplasm
Similarity search - Function
: / Cys/Met metabolism enzymes pyridoxal-phosphate attachment site. / Cys/Met metabolism, pyridoxal phosphate-dependent enzyme / Cys/Met metabolism PLP-dependent enzyme / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Cystathionine gamma-lyase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.52 Å
AuthorsUchikawa E / Nazi S / So A / Driss E
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_52956.png

Downloads & links

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Map

FileDownload / File: emd_52956.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 280 pix.
= 259.28 Å		0.93 Å/pix.
x 280 pix.
= 259.28 Å		0.93 Å/pix.
x 280 pix.
= 259.28 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.926 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.03216147 - 0.057731636
Average (Standard dev.)0.000036622776 (±0.0014713049)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 259.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52956_msk_1.map
Projections & Slices
AxesZYX

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Additional map: non sharpened

Fileemd_52956_additional_1.map
Annotationnon sharpened
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Half map: #1

Fileemd_52956_half_map_1.map
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Half map: #2

Fileemd_52956_half_map_2.map
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Sample components

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Entire : Complex of Cystathionine gamma-lyase and ZHAWOC24000

EntireName: Complex of Cystathionine gamma-lyase and ZHAWOC24000
Components
  • Complex: Complex of Cystathionine gamma-lyase and ZHAWOC24000
    • Protein or peptide: Cystathionine gamma-lyase

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Supramolecule #1: Complex of Cystathionine gamma-lyase and ZHAWOC24000

SupramoleculeName: Complex of Cystathionine gamma-lyase and ZHAWOC24000 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: tetramer
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Macromolecule #1: Cystathionine gamma-lyase

MacromoleculeName: Cystathionine gamma-lyase / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSHHHHHHS GLEVLFQGPM QEKDASSQGF LPHFQHFATQ AIHVGQDPEQ WTSRAVVPPI SLSTTFKQGA PGQHSGFEYS RSGNPTRNCL EKAVAALDGA KYCLAFASGL AATVTITHLL KAGDQIICMD DVYGGTNRYF RQVASEFGLK ISFVDCSKIK LLEAAITPET ...String:
MGSHHHHHHS GLEVLFQGPM QEKDASSQGF LPHFQHFATQ AIHVGQDPEQ WTSRAVVPPI SLSTTFKQGA PGQHSGFEYS RSGNPTRNCL EKAVAALDGA KYCLAFASGL AATVTITHLL KAGDQIICMD DVYGGTNRYF RQVASEFGLK ISFVDCSKIK LLEAAITPET KLVWIETPTN PTQKVIDIEG CAHIVHKHGD IILVVDNTFM SPYFQRPLAL GADISMYSAT KYMNGHSDVV MGLVSVNCES LHNRLRFLQN SLGAVPSPID CYLCNRGLKT LHVRMEKHFK NGMAVAQFLE SNPWVEKVIY PGLPSHPQHE LVKRQCTGCT GMVTFYIKGT LQHAEIFLKN LKLFTLAESL GGFESLAELP AIMTHASVLK NDRDVLGISD TLIRLSVGLE DEEDLLEDLD QALKAAHPPS GSHS

UniProtKB: Cystathionine gamma-lyase

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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
1.0 mMC19H23N7O2ZHAW24000
GridModel: SPT Labtech self-wicking R1.2/0.8 / Material: COPPER / Mesh: 300 / 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 GLACIOS
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: 6340 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 20.0 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

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Image processing

Particle selectionNumber selected: 5991531
CTF correctionSoftware - Name: RELION (ver. 4.0.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: D2 (2x2 fold dihedral) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.52 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 1743889
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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