期刊
CHEMBIOCHEM
卷 11, 期 5, 页码 673-680出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.200900750
关键词
antitumor agents; aza sugar; glycosidases; inhibitors; X-ray diffraction
资金
- National Science Foundation [DMR-0225180]
- National Institutes of Health, through its National Center for Research Resources [RR-01646]
- Canadian Institutes for Health Research [MOP79312]
- Mizutani Foundation [080032]
- Grants-in-Aid for Scientific Research [21390033] Funding Source: KAKEN
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 5 alpha-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.
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