8ZEQ

Molecular Architecture of Human Glycogen Debranching Enzyme: Insights into Glycogen Storage Disease III Pathogenesis

Summary for 8ZEQ

• Entry DOI: 10.2210/pdb8zeq/pdb
• EMDB information: 60043
• Descriptor: Glycogen debranching enzyme (1 entity in total)
• Functional Keywords: glycogen metabolism, glycogen debranching, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 174974.88

Authors

Guan, H.,Chen, H. (deposition date: 2024-05-06, release date: 2025-05-14, Last modification date: 2025-12-03)

Primary citation

Guan, H.,Chen, H.,Geng, H.,Ma, R.,Liu, Z.,Wang, Y.,Chen, Y.,Yan, K.
Molecular architecture and catalytic mechanism of human glycogen debranching enzyme.
Nat Commun, 16:5962-5962, 2025

PubMed Abstract: Glycogen, a key branched glucose polymer, acts as a vital energy reservoir in mammalian cells, particularly during intense activity or fasting. The glycogen debranching enzyme (GDE) plays a key role in glycogen degradation by removing branches, ensuring efficient glucose release. Dysfunction of GDE leads to the accumulation of limit dextrin and is implicated in the pathogenesis of Glycogen Storage Disease Type III (GSD III). We present the cryo-EM structure of human GDE (hsGDE) at 3.23 Å resolution, providing molecular insights into its substrate selectivity and catalytic mechanism. Our study further investigates the molecular consequences of disease-associated mutations by correlating structural data with enzymatic activities of representative GSD III-causing variants. We discover that these mutations induce GSD III through diverse mechanisms, including significant reductions in enzymatic activity, and disruptions to the glycogen-bound region and overall structural integrity. The elucidation of these pathways not only advances our understanding of hsGDE's role in substrate recognition and catalysis but also illuminates the molecular pathology of GSD III. Our findings pave the way for the development of targeted therapeutic strategies for this disease.

PubMed: 40593796
DOI: 10.1038/s41467-025-61077-6

Experimental method

ELECTRON MICROSCOPY (3.36 Å)