4UR9

Structure of ligand bound glycosylhydrolase

Summary for 4UR9

• Entry DOI: 10.2210/pdb4ur9/pdb
• Descriptor: O-GLCNACASE BT_4395, 4-ethoxyquinazoline, O-(2-ACETAMIDO-2-DEOXY D-GLUCOPYRANOSYLIDENE) AMINO-N-PHENYLCARBAMATE, ... (5 entities in total)
• Functional Keywords: hydrolase
• Biological source: BACTEROIDES THETAIOTAOMICRON
• Total number of polymer chains: 2
• Total formula weight: 165727.35

Authors

Darby, J.F.,Landstroem, J.,Roth, C.,He, Y.,Schultz, M.,Davies, G.J.,Hubbard, R.E. (deposition date: 2014-06-27, release date: 2015-02-25, Last modification date: 2024-05-08)

Primary citation

Darby, J.F.,Landstrom, J.,Roth, C.,He, Y.,Davies, G.J.,Hubbard, R.E.
Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase.
Angew.Chem.Int.Ed.Engl., 53:13419-, 2014

PubMed Abstract: Fragment-based approaches are used routinely to discover enzyme inhibitors as cellular tools and potential therapeutic agents. There have been few reports, however, of the discovery of small-molecule enzyme activators. Herein, we describe the discovery and characterization of small-molecule activators of a glycoside hydrolase (a bacterial O-GlcNAc hydrolase). A ligand-observed NMR screen of a library of commercially available fragments identified an enzyme activator which yielded an approximate 90 % increase in kcat /KM  values (kcat =catalytic rate constant; KM =Michaelis constant). This compound binds to the enzyme in close proximity to the catalytic center. Evolution of the initial hits led to improved compounds that behave as nonessential activators effecting both KM  and Vmax  values (Vmax =maximum rate of reaction). The compounds appear to stabilize an active "closed" form of the enzyme. Such activators could offer an orthogonal alternative to enzyme inhibitors for perturbation of enzyme activity in vivo, and could also be used for glycoside hydrolase activation in many industrial processes.

PubMed: 25291993
DOI: 10.1002/ANIE.201407081

Experimental method

X-RAY DIFFRACTION (2.2 Å)