2W67

BtGH84 in complex with FMA34

Summary for 2W67

• Entry DOI: 10.2210/pdb2w67/pdb
• Related: 2CHN 2CHO 2J47 2J4G 2JIW 2VVN 2VVS 2VW3 2W4X 2W66
• Descriptor: O-GLCNACASE BT_4395, N-[(3S,4R,5R,6R)-4,5,6-trihydroxyazepan-3-yl]acetamide, GLYCEROL, ... (5 entities in total)
• Functional Keywords: glycoside hydrolase, complex, hydrolase, inhibitor, glycosidase
• Biological source: BACTEROIDES THETAIOTAOMICRON VPI-5482
• Total number of polymer chains: 2
• Total formula weight: 165212.92

Authors

He, Y.,Davies, G.J. (deposition date: 2008-12-17, release date: 2009-04-14, Last modification date: 2023-12-13)

Primary citation

Marcelo, F.,He, Y.,Yuzwa, S.A.,Nieto, L.,Jimenez-Barbero, J.,Sollogoub, M.,Vocadlo, D.J.,Davies, G.J.,Bleriot, Y.
Molecular Basis for Inhibition of Gh84 Glycoside Hydrolases by Substituted Azepanes: Conformational Flexibility Enables Probing of Substrate Distortion.
J.Am.Chem.Soc., 131:5390-, 2009

PubMed Abstract: Here we report the synthesis of a series of polyhydroxylated 3- and 5-acetamido azepanes and detail the molecular basis of their inhibition of family 84 glycoside hydrolases. These family 84 enzymes include human O-GlcNAcase, an enzyme involved in post-translational processing of intracellular proteins modified by O-linked beta-N-acetylglucosamine residues. Detailed structural analysis of the binding of these azepanes to BtGH84, a bacterial homologue of O-GlcNAcase, highlights their conformational flexibility. Molecular mechanics and molecular dynamics calculations reveal that binding to the enzyme involves significant conformational distortion of these inhibitors from their preferred solution conformations. The binding of these azepanes provides structural insight into substrate distortion that likely occurs along the reaction coordinate followed by O-GlcNAcase during glycoside hydrolysis. This class of inhibitors may prove to be useful probes for evaluating the conformational itineraries of glycosidases and aid the development of more potent and specific glycosidase inhibitors.

PubMed: 19331390
DOI: 10.1021/JA809776R

Experimental method

X-RAY DIFFRACTION (2.25 Å)