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- PDB-8gv3: The cryo-EM structure of GSNOR with NYY001 -

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Basic information

Entry
Database: PDB / ID: 8gv3
TitleThe cryo-EM structure of GSNOR with NYY001
ComponentsAlcohol dehydrogenase class-3
KeywordsOXIDOREDUCTASE / Alcohol dehydrogenase class-3
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
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Chem-WKZ / Alcohol dehydrogenase class-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single 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, 2items
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, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release
Revision 1.0Sep 20, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Sep 20, 2023Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Sep 20, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Sep 20, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Sep 20, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 20, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alcohol dehydrogenase class-3
B: Alcohol dehydrogenase class-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,39010
Polymers79,8032
Non-polymers2,5888
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Alcohol dehydrogenase class-3 / Alcohol dehydrogenase 5 / Alcohol dehydrogenase class chi chain / Alcohol dehydrogenase class-III / ...Alcohol dehydrogenase 5 / Alcohol dehydrogenase class chi chain / Alcohol dehydrogenase class-III / Glutathione-dependent formaldehyde dehydrogenase / FALDH / FDH / GSH-FDH / S-(hydroxymethyl)glutathione dehydrogenase


Mass: 39901.305 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADH5, ADHX, FDH / Production host: Homo sapiens (human)
References: UniProt: P11766, alcohol dehydrogenase, Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor, S-(hydroxymethyl)glutathione dehydrogenase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#4: Chemical 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


Mass: 499.584 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H25N5O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: Alcohol dehydrogenase class-3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 26000 nm / Nominal defocus min: 10000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 288334 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0075836
ELECTRON MICROSCOPYf_angle_d0.6647918
ELECTRON MICROSCOPYf_dihedral_angle_d8.712810
ELECTRON MICROSCOPYf_chiral_restr0.051908
ELECTRON MICROSCOPYf_plane_restr0.005992

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