The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A

Chembiochem. 2009 Jan 26;10(2):268-77. doi: 10.1002/cbic.200800538.


Mannostatin A is a potent inhibitor of the mannose-trimming enzyme, Golgi alpha-mannosidase II (GMII), which acts late in the N-glycan processing pathway. Inhibition of this enzyme provides a route to blocking the transformation-associated changes in cancer cell surface oligosaccharide structures. Here, we report on the synthesis of new Mannostatin derivatives and analyze their binding in the active site of Drosophila GMII by X-ray crystallography. The results indicate that the interaction with the backbone carbonyl of Arg876 is crucial to the high potency of the inhibitor-an effect enhanced by the hydrophobic interaction between the thiomethyl group and an aromatic pocket vicinal to the cleavage site. The various structures indicate that differences in the hydration of protein-ligand complexes are also important determinants of plasticity as well as selectivity of inhibitor binding.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cyclopentanes / chemical synthesis
  • Cyclopentanes / chemistry
  • Cyclopentanes / metabolism
  • Cyclopentanes / pharmacology*
  • Drosophila melanogaster / enzymology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Hydrophobic and Hydrophilic Interactions
  • Mannosidases / antagonists & inhibitors*
  • Mannosidases / chemistry
  • Mannosidases / metabolism
  • Substrate Specificity
  • Sulfur / chemistry


  • Cyclopentanes
  • Enzyme Inhibitors
  • mannostatin A
  • Sulfur
  • Mannosidases
  • mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase

Associated data

  • PDB/3D4Y
  • PDB/3D4Z
  • PDB/3D50
  • PDB/3D51
  • PDB/3D52