4JFT: Crystal Structure Of A Bacterial Fucosidase With Iminosugar Inhibitor N-desmethyl-4-epi-(+)-codonopsinine

Citation:
Abstract
Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking (3)E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100% inhibition of the proliferation of MDA-MB-231 cancer cells at 50 muM.
PDB ID: 4JFTDownload
MMDB ID: 113556
PDB Deposition Date: 2013/2/28
Updated in MMDB: 2013/09
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4JFT: monomeric; determined by author
Molecular Components in 4JFT
Label Count Molecule
Protein (1 molecule)
1
Alpha-l-fucosidase
Molecule annotation
Chemicals (10 molecules)
1
1
2
2
3
3
4
4
* Click molecule labels to explore molecular sequence information.

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