6RRW
GOLGI ALPHA-MANNOSIDASE II in complex with (2R,3R,4R,5S)-1-(5-{[4-(3,4-Dihydro-2H-1,5-benzodioxepin-7-yl)benzyl]oxy}pentyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol
Summary for 6RRW
Entry DOI | 10.2210/pdb6rrw/pdb |
Descriptor | Alpha-mannosidase 2, (2~{R},3~{R},4~{R},5~{S})-1-[5-[[4-(3,4-dihydro-2~{H}-1,5-benzodioxepin-7-yl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol, ZINC ION, ... (4 entities in total) |
Functional Keywords | mannosidase, glycoside hydrolase, hydrolase |
Biological source | Drosophila melanogaster (Fruit fly) |
Total number of polymer chains | 1 |
Total formula weight | 118760.99 |
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: 2024-11-13) |
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 Cited by 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: 32605368DOI: 10.1021/jacs.0c03880 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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