9FTR

Drosophila golgi alpha-mannosidase II (dGMII) in complex with amide modified swainsonine-configured alkyl indolizidine

これはPDB形式変換不可エントリーです。

9FTR の概要

• エントリーDOI: 10.2210/pdb9ftr/pdb
• 分子名称: Alpha-mannosidase 2, amide modified swainsonine-configured alkyl indolizidine, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: inhibitor, glycosyl hydrolase, hydrolase
• 由来する生物種: Drosophila melanogaster (fruit fly)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 119926.28

構造登録者

Bennett, M.,Koemans, T.,Overkleeft, H.S.,Davies, G.J. (登録日: 2024-06-25, 公開日: 2024-10-09, 最終更新日: 2024-10-23)

主引用文献

Koemans, T.,Bennett, M.,Ferraz, M.J.,Armstrong, Z.,Artola, M.,Aerts, J.M.F.G.,Codee, J.D.C.,Overkleeft, H.S.,Davies, G.J.
Structure-guided design of C3-branched swainsonine as potent and selective human Golgi alpha-mannosidase (GMII) inhibitor.
Chem.Commun.(Camb.), 60:11734-11737, 2024

PubMed Abstract: The human Golgi α-mannosidase, hGMII, removes two mannose residues from GlcNAc-ManGlcNAc to produce GlcNAcManGlcNAc, the precursor of all complex -glycans including tumour-associated ones. The natural product GMII inhibitor, swainsonine, blocks processing of cancer-associated -glycans, but also inhibits the four other human α-mannosidases, rendering it unsuitable for clinical use. Our previous structure-guided screening of iminosugar pyrrolidine and piperidine fragments identified two micromolar hGMII inhibitors occupying the enzyme active pockets in adjacent, partially overlapping sites. Here we demonstrate that fusing these fragments yields swainsonine-configured indolizidines featuring a C3-substituent that act as selective hGMII inhibitors. Our structure-guided GMII-selective inhibitor design complements a recent combinatorial approach that yielded similarly configured and substituted indolizidine GMII inhibitors, and holds promise for the potential future development of anti-cancer agents targeting Golgi -glycan processing.

PubMed: 39318342
DOI: 10.1039/d4cc04514a

実験手法

X-RAY DIFFRACTION (2.14 Å)