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

Jean M.H. Van Den Elsen, Douglas A. Kuntz, David R. Rose

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

Golgi α-mannosidase II, a key enzyme in N-glycan processing, is a target in the development of anticancer 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 GlcNAcMan5GlcNAc2 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.

Original languageEnglish
Pages (from-to)3008-3017
Number of pages10
JournalEMBO Journal
Volume20
Issue number12
DOIs
Publication statusPublished - 15 Jun 2001

Keywords

  • Cancer therapy
  • Drug design
  • Golgi α-mannosidase II
  • N-glycosylation pathway
  • X-ray crystallography

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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