2XPK

Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases

Summary for 2XPK

• Entry DOI: 10.2210/pdb2xpk/pdb
• Related: 2CBI 2CBJ 2J62 2JH2 2V5C 2V5D 2VUR 2WB5 2X0Y
• Descriptor: O-GLCNACASE NAGJ, N-[(5R,6R,7R,8S)-6,7-DIHYDROXY-5-(HYDROXYMETHYL)-2-(2-PHENYLETHYL)-5,6,7,8-TETRAHYDROIMIDAZO[1,2-A]PYRIDIN-8-YL]-3-SULFANYLPROPANAMIDE (3 entities in total)
• Functional Keywords: hydrolase, signalling
• Biological source: CLOSTRIDIUM PERFRINGENS
• Total number of polymer chains: 2
• Total formula weight: 134170.38

Authors

Dorfmueller, H.C.,Borodkin, V.S.,Schimpl, M.,Zheng, X.,Kime, R.,Read, K.D.,van Aalten, D.M.F. (deposition date: 2010-08-26, release date: 2011-03-16, Last modification date: 2023-12-20)

Primary citation

Dorfmueller, H.C.,Borodkin, V.S.,Schimpl, M.,Zheng, X.,Kime, R.,Read, K.D.,Van Aalten, D.M.F.
Cell-Penetrant, Nanomolar O-Glcnacase Inhibitors Selective Against Lysosomal Hexosaminidases.
Chem.Biol, 17:1250-, 2010

PubMed Abstract: Posttranslational modification of metazoan nucleocytoplasmic proteins with N-acetylglucosamine (O-GlcNAc) is essential, dynamic, and inducible and can compete with protein phosphorylation in signal transduction. Inhibitors of O-GlcNAcase, the enzyme removing O-GlcNAc, are useful tools for studying the role of O-GlcNAc in a range of cellular processes. We report the discovery of nanomolar OGA inhibitors that are up to 900,000-fold selective over the related lysosomal hexosaminidases. When applied at nanomolar concentrations on live cells, these cell-penetrant molecules shift the O-GlcNAc equilibrium toward hyper-O-GlcNAcylation with EC₅₀ values down to 3 nM and are thus invaluable tools for the study of O-GlcNAc cell biology.

PubMed: 21095575
DOI: 10.1016/J.CHEMBIOL.2010.09.014

Experimental method

X-RAY DIFFRACTION (2.4 Å)