3EJS: Golgi Alpha-mannosidase Ii In Complex With 5-substituted Swainsonine Analog: (5s)-5-[2'-(4-tert-butylphenyl)ethyl]-swainsonine

Citation:
Abstract
Golgi alpha-mannosidase II (GMII) is a key enzyme in the N-glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5alpha-substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X-ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head-group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well-organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N-acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors.
PDB ID: 3EJSDownload
MMDB ID: 77280
PDB Deposition Date: 2008/9/18
Updated in MMDB: 2009/10
Experimental Method:
x-ray diffraction
Resolution: 1.35  Å
Source Organism:
Similar Structures:
Biological Unit for 3EJS: monomeric; determined by author and by software (PISA)
Molecular Components in 3EJS
Label Count Molecule
Protein (1 molecule)
1
Alpha-mannosidase 2(Gene symbol: alpha-Man-IIa)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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