Structure of Golgi α-mannosidase II: a target for inhibition of growth and metastasis of cancer cells

• Published in: The EMBO journal 2001-06, Vol.20 (12), p.3008-3017
• Main Authors: van den Elsen, Jean M.H., Kuntz, Douglas A., Rose, David R.
• Format: Article
• Language: English
• Subjects: 1-Deoxynojirimycin - pharmacology; Amino Acid Sequence; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Binding Sites; cancer therapy; Catalysis; Cell Division; Cell Line; Crystallography, X-Ray; Drosophila melanogaster - chemistry; drug design; Enzyme Inhibitors - pharmacology; Gene Expression; Golgi α-mannosidase II; Mannosidases - antagonists & inhibitors; Mannosidases - chemistry; Mannosidases - genetics; Models, Molecular; Molecular Sequence Data; N-glycosylation pathway; Neoplasm Metastasis; Protein Structure, Secondary; Substrate Specificity; Swainsonine - pharmacology; Tumor Cells, Cultured; X-ray crystallography
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/20.12.3008

Golgi α‐mannosidase II, a key enzyme in N ‐glycan processing, is a target in the development of anti‐ cancer therapies. The crystal structure of Drosophila Golgi α‐mannosidase II in the absence and presence of the anti‐cancer agent swainsonine and the inhibitor deoxymannojirimycin reveals a novel protein fold with an active site zinc intricately involved both in the substrate specificity of the enzyme and directly in the catalytic mechanism. Identification of a putative GlcNAc binding pocket in the vicinity of the active site cavity provides a model for the binding of the GlcNAcMan 5 GlcNAc 2 substrate and the consecutive hydrolysis of the α1,6‐ and α1,3‐linked mannose residues. The enzyme–inhibitor interactions observed provide insight into the catalytic mechanism, opening the door to the design of novel inhibitors of α‐mannosidase II.