8GV3

The cryo-EM structure of GSNOR with NYY001

Summary for 8GV3

• Entry DOI: 10.2210/pdb8gv3/pdb
• EMDB information: 34282
• Descriptor: Alcohol dehydrogenase class-3, ZINC ION, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: alcohol dehydrogenase class-3, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 82390.26

Authors

Xia, Y.,Zhang, Q.,Yao, D.,Zhao, S.,Xie, L.,Ji, Y.,Cao, Y. (deposition date: 2022-09-14, release date: 2023-09-20, Last modification date: 2025-10-08)

Primary citation

Zhao, S.,Song, T.,Tang, X.,Fan, C.,Yang, Y.,Zhang, Z.,Xia, Y.,Zhang, Y.,Cao, J.,Wang, Z.,Shi, Z.,Tang, X.,Wang, D.,Yin, G.,Zhang, S.,Gao, Y.,Chen, H.,Wang, L.,Chen, F.,Wang, H.,Yu, B.,Cao, Y.,Sun, K.,Liu, X.,Wang, X.,Yan, C.,Han, Y.,Han, Y.,Xie, L.,Ji, Y.
S -nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models.
Sci Transl Med, 17:eadn9216-eadn9216, 2025

PubMed 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 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.

PubMed: 41032622
DOI: 10.1126/scitranslmed.adn9216

Experimental method

ELECTRON MICROSCOPY (3.05 Å)