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- EMDB-34282: The cryo-EM structure of GSNOR with NYY001 -

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Basic information

Entry
Database: EMDB / ID: EMD-34282
TitleThe cryo-EM structure of GSNOR with NYY001
Map data
Sample
  • Complex: Alcohol dehydrogenase class-3
    • Protein or peptide: Alcohol dehydrogenase class-3
  • Ligand: ZINC ION
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: (4P)-4-{2-[4-(1H-imidazol-1-yl)phenyl]-5-[3-oxo-3-(2-oxo-1,3-thiazolidin-3-yl)propyl]-1H-pyrrol-1-yl}-3-methylbenzamide
KeywordsAlcohol dehydrogenase class-3 / OXIDOREDUCTASE
Function / homology
Function and homology information


formaldehyde dehydrogenase (NAD+) activity / S-nitrosoglutathione reductase (NADH) activity / S-(hydroxymethyl)glutathione dehydrogenase (NADP+) activity / S-(hydroxymethyl)glutathione dehydrogenase (NAD+) activity / S-(hydroxymethyl)glutathione dehydrogenase / fatty acid omega-oxidation / S-(hydroxymethyl)glutathione dehydrogenase [NAD(P)+] activity / response to nitrosative stress / formaldehyde catabolic process / Ethanol oxidation ...formaldehyde dehydrogenase (NAD+) activity / S-nitrosoglutathione reductase (NADH) activity / S-(hydroxymethyl)glutathione dehydrogenase (NADP+) activity / S-(hydroxymethyl)glutathione dehydrogenase (NAD+) activity / S-(hydroxymethyl)glutathione dehydrogenase / fatty acid omega-oxidation / S-(hydroxymethyl)glutathione dehydrogenase [NAD(P)+] activity / response to nitrosative stress / formaldehyde catabolic process / Ethanol oxidation / alcohol dehydrogenase (NAD+) activity / positive regulation of blood pressure / alcohol dehydrogenase / respiratory system process / Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor / response to redox state / retinoid metabolic process / fatty acid binding / response to lipopolysaccharide / electron transfer activity / mitochondrion / extracellular exosome / zinc ion binding / identical protein binding / cytosol
Similarity search - Function
Alcohol dehydrogenase class III / Alcohol dehydrogenase, zinc-type, conserved site / Zinc-containing alcohol dehydrogenases signature. / Alcohol dehydrogenase-like, C-terminal / Zinc-binding dehydrogenase / Alcohol dehydrogenase, N-terminal / Alcohol dehydrogenase GroES-like domain / GroES-like superfamily / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
Alcohol dehydrogenase class-3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsXia Y / Zhang Q / Yao D / Zhao S / Xie L / Ji Y / Cao Y
Funding support China, 2 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFC1004704 China
National Natural Science Foundation of China (NSFC)82072468 China
CitationJournal: Sci Transl Med / Year: 2025
Title: -nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models.
Authors: Shuang Zhao / Tianyu Song / Xin Tang / Chenglin Fan / Yuhao Yang / Zhiren Zhang / Ying Xia / Yan Zhang / Jiawei Cao / Ziyu Wang / Zhiguang Shi / Xinlong Tang / Dongjin Wang / Guoyong Yin / ...Authors: Shuang Zhao / Tianyu Song / Xin Tang / Chenglin Fan / Yuhao Yang / Zhiren Zhang / Ying Xia / Yan Zhang / Jiawei Cao / Ziyu Wang / Zhiguang Shi / Xinlong Tang / Dongjin Wang / Guoyong Yin / Shaohua Zhang / Yuanqing Gao / Hongshan Chen / Liansheng Wang / Feng Chen / Hong Wang / Bo Yu / Yu Cao / Kangyun Sun / Xin Liu / Xiujie Wang / Chenghui Yan / Yaling Han / Yi Han / Liping Xie / Yong Ji /
Abstract: Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We ...Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We identified up-regulated -nitrosoglutathione reductase (GSNOR) as a critical factor associated with diabetic vascular complications by unbiased proteomics. Elevated GSNOR expression was observed in the endothelium of patients with type 2 diabetes and in streptozotocin (STZ)-induced type 1 diabetes mice as well as in type 2 diabetes mouse models. Genetic ablation of endothelial promoted angiogenesis, maintained vascular permeability, and improved vasodilation in type 1 diabetes mice induced by STZ. GSNOR deficiency protected against high glucose-induced endothelial dysfunction in vitro, as evidenced by rescued tube formation, enhanced spheroid sprouting, maintained barrier integrity, and reduced permeability. Mechanistically, GSNOR orchestrated endothelial dysfunction independently of its enzymatic activity by binding the transcription factor ETS-related gene (ERG) and triggered its nuclear export through chromosome region maintenance 1. We synthesized NYY-001, an oral agent, that selectively blocks the GSNOR-ERG interaction. The direct targeting of NYY-001 to GSNOR was determined by resolving the crystal structure of their complex using cryo-electron microscopy. NYY-001 treatment enhanced postischemic neovascularization and restored vascular permeability in the peripheral vasculature in STZ-induced type 1 diabetes and type 2 diabetes mouse models. These findings reveal a mechanistic role for the GSNOR-ERG complex in diabetic vascular complications and highlight NYY-001 as a promising therapeutic candidate.
History
DepositionSep 14, 2022-
Header (metadata) releaseSep 20, 2023-
Map releaseSep 20, 2023-
UpdateOct 8, 2025-
Current statusOct 8, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_34282.png

Downloads & links

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Map

FileDownload / File: emd_34282.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 180 pix.
= 198. Å		1.1 Å/pix.
x 180 pix.
= 198. Å		1.1 Å/pix.
x 180 pix.
= 198. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-5.132504 - 8.057048999999999
Average (Standard dev.)-0.0021636556 (±0.2376401)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 198.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34282_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34282_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Alcohol dehydrogenase class-3

EntireName: Alcohol dehydrogenase class-3
Components
  • Complex: Alcohol dehydrogenase class-3
    • Protein or peptide: Alcohol dehydrogenase class-3
  • Ligand: ZINC ION
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: (4P)-4-{2-[4-(1H-imidazol-1-yl)phenyl]-5-[3-oxo-3-(2-oxo-1,3-thiazolidin-3-yl)propyl]-1H-pyrrol-1-yl}-3-methylbenzamide

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Supramolecule #1: Alcohol dehydrogenase class-3

SupramoleculeName: Alcohol dehydrogenase class-3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alcohol dehydrogenase class-3

MacromoleculeName: Alcohol dehydrogenase class-3 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: alcohol dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.901305 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MANEVIKCKA AVAWEAGKPL SIEEIEVAPP KAHEVRIKII ATAVCHTDAY TLSGADPEGC FPVILGHEGA GIVESVGEGV TKLKAGDTV IPLYIPQCGE CKFCLNPKTN LCQKIRVTQG KGLMPDGTSR FTCKGKTILH YMGTSTFSEY TVVADISVAK I DPLAPLDK ...String:
MANEVIKCKA AVAWEAGKPL SIEEIEVAPP KAHEVRIKII ATAVCHTDAY TLSGADPEGC FPVILGHEGA GIVESVGEGV TKLKAGDTV IPLYIPQCGE CKFCLNPKTN LCQKIRVTQG KGLMPDGTSR FTCKGKTILH YMGTSTFSEY TVVADISVAK I DPLAPLDK VCLLGCGIST GYGAAVNTAK LEPGSVCAVF GLGGVGLAVI MGCKVAGASR IIGVDINKDK FARAKEFGAT EC INPQDFS KPIQEVLIEM TDGGVDYSFE CIGNVKVMRA ALEACHKGWG VSVVVGVAAS GEEIATRPFQ LVTGRTWKGT AFG GWKSVE SVPKLVSEYM SKKIKVDEFV THNLSFDEIN KAFELMHSGK SIRTVVKIE

UniProtKB: Alcohol dehydrogenase class-3

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #3: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

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Macromolecule #4: (4P)-4-{2-[4-(1H-imidazol-1-yl)phenyl]-5-[3-oxo-3-(2-oxo-1,3-thia...

MacromoleculeName: (4P)-4-{2-[4-(1H-imidazol-1-yl)phenyl]-5-[3-oxo-3-(2-oxo-1,3-thiazolidin-3-yl)propyl]-1H-pyrrol-1-yl}-3-methylbenzamide
type: ligand / ID: 4 / Number of copies: 2 / Formula: WKZ
Molecular weightTheoretical: 499.584 Da
Chemical component information

ChemComp-WKZ:
(4P)-4-{2-[4-(1H-imidazol-1-yl)phenyl]-5-[3-oxo-3-(2-oxo-1,3-thiazolidin-3-yl)propyl]-1H-pyrrol-1-yl}-3-methylbenzamide

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 26.0 µm / Nominal defocus min: 10.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 288334
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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