6RS0

GOLGI ALPHA-MANNOSIDASE II in complex with (2S,3S,4R,5R)-1-(2-(Benzyloxy)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

Summary for 6RS0

• Entry DOI: 10.2210/pdb6rs0/pdb
• Descriptor: Alpha-mannosidase 2, ZINC ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: mannosidase, glycoside hydrolase, hydrolase
• Biological source: Drosophila melanogaster (Fruit fly)
• Total number of polymer chains: 1
• Total formula weight: 118694.89

Authors

Armstrong, Z.,Lahav, D.,Johnson, R.,Kuo, C.L.,Beenakker, T.J.M.,de Boer, C.,Wong, C.S.,van Rijssel, E.R.,Debets, M.,Geurink, P.P.,Ovaa, H.,van der Stelt, M.,Codee, J.D.C.,Aerts, J.M.F.G.,Wu, L.,Overkleeft, H.S.,Davies, G.J. (deposition date: 2019-05-20, release date: 2020-07-08, Last modification date: 2024-10-23)

Primary citation

Armstrong, Z.,Kuo, C.L.,Lahav, D.,Liu, B.,Johnson, R.,Beenakker, T.J.M.,de Boer, C.,Wong, C.S.,van Rijssel, E.R.,Debets, M.F.,Florea, B.I.,Hissink, C.,Boot, R.G.,Geurink, P.P.,Ovaa, H.,van der Stelt, M.,van der Marel, G.M.,Codee, J.D.C.,Aerts, J.M.F.G.,Wu, L.,Overkleeft, H.S.,Davies, G.J.
Manno- epi -cyclophellitols Enable Activity-Based Protein Profiling of Human alpha-Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors.
J.Am.Chem.Soc., 142:13021-13029, 2020

PubMed Abstract: Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcManGlcNAc to produce GlcNAcManGlcNAc, the precursor for all complex -glycans, including the branched -glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce α-mannosidosis-like symptoms. Despite many structural and mechanistic studies of GMII, we still lack a potent and selective inhibitor of this enzyme. Here, we synthesized manno--cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno--cyclophellitol aziridine derivatives enabled activity-based protein profiling of α-mannosidases from both human cell lysate and mouse tissue extracts. Synthesized probes also facilitated a fluorescence polarization-based screen for dGMII inhibitors. We identified seven previously unknown inhibitors of GMII from a library of over 350 iminosugars and investigated their binding modalities through X-ray crystallography. Our results reveal previously unobserved inhibitor binding modes and promising scaffolds for the generation of selective GMII inhibitors.

PubMed: 32605368
DOI: 10.1021/jacs.0c03880

Experimental method

X-RAY DIFFRACTION (1.8 Å)