2WVT

Crystal structure of an alpha-L-fucosidase GH29 from Bacteroides thetaiotaomicron in complex with a novel iminosugar fucosidase inhibitor

Summary for 2WVT

• Entry DOI: 10.2210/pdb2wvt/pdb
• Related: 2WVS 2WVU 2WVV
• Descriptor: ALPHA-L-FUCOSIDASE, (2S,3R,5R,6S)-3,4,5-TRIHYDROXY-2,6-BIS(HYDROXYMETHYL)PIPERIDINIUM, GLYCEROL, ... (5 entities in total)
• Functional Keywords: hydrolase, alpha-l-fucose, glycoside hydrolase family 29
• Biological source: BACTEROIDES THETAIOTAOMICRON
• Total number of polymer chains: 2
• Total formula weight: 103787.46

Authors

Lammerts van Bueren, A.,Ardevol, A.,Fayers-Kerr, J.,Luo, B.,Zhang, Y.,Sollogoub, M.,Bleriot, Y.,Rovira, C.,Davies, G.J. (deposition date: 2009-10-20, release date: 2010-02-02, Last modification date: 2023-12-20)

Primary citation

Lammerts Van Bueren, A.,Ardevol, A.,Fayers-Kerr, J.,Luo, B.,Zhang, Y.,Sollogoub, M.,Bleriot, Y.,Rovira, C.,Davies, G.J.
Analysis of the Reaction Coordinate of Alpha-L-Fucosidases: A Combined Structural and Quantum Mechanical Approach.
J.Am.Chem.Soc., 132:1804-, 2010

PubMed Abstract: The enzymatic hydrolysis of alpha-L-fucosides is of importance in cancer, bacterial infections, and fucosidosis, a neurodegenerative lysosomal storage disorder. Here we show a series of snapshots along the reaction coordinate of a glycoside hydrolase family GH29 alpha-L-fucosidase unveiling a Michaelis (ES) complex in a (1)C(4) (chair) conformation and a covalent glycosyl-enzyme intermediate in (3)S(1) (skew-boat). First principles metadynamics simulations on isolated alpha-L-fucose strongly support a (1)C(4)<-->(3)H(4)<-->(3)S(1) conformational itinerary for the glycosylation step of the reaction mechanism and indicate a strong "preactivation" of the (1)C(4) complex to nucleophilic attack as reflected by free energy, C1-O1/O5-C1 bond length elongation/reduction, C1-O1 bond orientation, and positive charge development around the anomeric carbon. Analysis of an imino sugar inhibitor is consistent with tight binding of a chair-conformed charged species.

PubMed: 20092273
DOI: 10.1021/JA908908Q

Experimental method

X-RAY DIFFRACTION (1.8 Å)