論文

査読有り
2010年3月

Structural Investigation of the Binding of 5-Substituted Swainsonine Analogues to Golgi alpha-Mannosidase II

CHEMBIOCHEM
  • Douglas A. Kuntz
  • ,
  • Shinichi Nakayama
  • ,
  • Kayla Shea
  • ,
  • Hitoshi Hori
  • ,
  • Yoshihiro Uto
  • ,
  • Hideko Nagasawa
  • ,
  • David. R. Rose

11
5
開始ページ
673
終了ページ
680
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/cbic.200900750
出版者・発行元
WILEY-V C H VERLAG GMBH

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.

Web of Science ® 被引用回数 : 21

リンク情報
DOI
https://doi.org/10.1002/cbic.200900750
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/20209559
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000276536000010&DestApp=WOS_CPL