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==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== | ==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== | ||
<StructureSection load='6rrw' size='340' side='right'caption='[[6rrw]]' scene=''> | <StructureSection load='6rrw' size='340' side='right'caption='[[6rrw]], [[Resolution|resolution]] 2.15Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RRW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RRW FirstGlance]. <br> | <table><tr><td colspan='2'>[[6rrw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Drome Drome]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RRW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RRW FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rrw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rrw OCA], [http://pdbe.org/6rrw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rrw RCSB], [http://www.ebi.ac.uk/pdbsum/6rrw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rrw ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KG5:(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'>KG5</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">alpha-Man-IIa, GmII, CG18802 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7227 DROME])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mannosyl-oligosaccharide_1,3-1,6-alpha-mannosidase Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.114 3.2.1.114] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rrw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rrw OCA], [http://pdbe.org/6rrw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rrw RCSB], [http://www.ebi.ac.uk/pdbsum/6rrw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rrw ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/MAN2_DROME MAN2_DROME]] Catalyzes the first committed step in the biosynthesis of complex N-glycans. It controls conversion of high mannose to complex N-glycans; the final hydrolytic step in the N-glycan maturation pathway (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce alpha-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-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of alpha-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. | |||
Manno-epi-cyclophellitols Enable Activity-Based Protein Profiling of Human alpha-Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors.,Armstrong Z, Kuo CL, Lahav D, Liu B, Johnson R, Beenakker TJM, de Boer C, Wong CS, van Rijssel ER, Debets MF, Florea BI, Hissink C, Boot RG, Geurink PP, Ovaa H, van der Stelt M, van der Marel GM, Codee JDC, Aerts JMFG, Wu L, Overkleeft HS, Davies GJ J Am Chem Soc. 2020 Jul 29;142(30):13021-13029. doi: 10.1021/jacs.0c03880. Epub, 2020 Jul 16. PMID:32605368<ref>PMID:32605368</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6rrw" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Mannosidase 3D structures|Mannosidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Drome]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Aerts | [[Category: Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase]] | ||
[[Category: Armstrong Z]] | [[Category: Aerts, J M.F G]] | ||
[[Category: Beenakker | [[Category: Armstrong, Z]] | ||
[[Category: Codee | [[Category: Beenakker, T J.M]] | ||
[[Category: Davies | [[Category: Boer, C de]] | ||
[[Category: Debets M]] | [[Category: Codee, J D.C]] | ||
[[Category: Geurink | [[Category: Davies, G J]] | ||
[[Category: Johnson R]] | [[Category: Debets, M]] | ||
[[Category: Kuo | [[Category: Geurink, P P]] | ||
[[Category: Lahav D]] | [[Category: Johnson, R]] | ||
[[Category: Ovaa H]] | [[Category: Kuo, C L]] | ||
[[Category: Overkleeft | [[Category: Lahav, D]] | ||
[[Category: Wong | [[Category: Ovaa, H]] | ||
[[Category: Wu L]] | [[Category: Overkleeft, H S]] | ||
[[Category: | [[Category: Rijssel, E R.van]] | ||
[[Category: | [[Category: Stelt, M van der]] | ||
[[Category: | [[Category: Wong, C S]] | ||
[[Category: Wu, L]] | |||
[[Category: Glycoside hydrolase]] | |||
[[Category: Hydrolase]] | |||
[[Category: Mannosidase]] | |||
Revision as of 11:19, 20 January 2021
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
Structural highlights
Function[MAN2_DROME] Catalyzes the first committed step in the biosynthesis of complex N-glycans. It controls conversion of high mannose to complex N-glycans; the final hydrolytic step in the N-glycan maturation pathway (By similarity). Publication Abstract from PubMedGolgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce alpha-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-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of alpha-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. Manno-epi-cyclophellitols Enable Activity-Based Protein Profiling of Human alpha-Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors.,Armstrong Z, Kuo CL, Lahav D, Liu B, Johnson R, Beenakker TJM, de Boer C, Wong CS, van Rijssel ER, Debets MF, Florea BI, Hissink C, Boot RG, Geurink PP, Ovaa H, van der Stelt M, van der Marel GM, Codee JDC, Aerts JMFG, Wu L, Overkleeft HS, Davies GJ J Am Chem Soc. 2020 Jul 29;142(30):13021-13029. doi: 10.1021/jacs.0c03880. Epub, 2020 Jul 16. PMID:32605368[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Drome
- Large Structures
- Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase
- Aerts, J M.F G
- Armstrong, Z
- Beenakker, T J.M
- Boer, C de
- Codee, J D.C
- Davies, G J
- Debets, M
- Geurink, P P
- Johnson, R
- Kuo, C L
- Lahav, D
- Ovaa, H
- Overkleeft, H S
- Rijssel, E R.van
- Stelt, M van der
- Wong, C S
- Wu, L
- Glycoside hydrolase
- Hydrolase
- Mannosidase