7kbj: Difference between revisions
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==Co-crystal structure of alpha glucosidase with compound 9== | |||
<StructureSection load='7kbj' size='340' side='right'caption='[[7kbj]], [[Resolution|resolution]] 2.21Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7kbj]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KBJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KBJ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.21Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=WAV:(1S,2S,3R,4S,5S)-1-(hydroxymethyl)-5-{[2-(2-{[2-nitro-4-(triazan-1-yl)phenyl]amino}ethoxy)ethyl]amino}cyclohexane-1,2,3,4-tetrol'>WAV</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7kbj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kbj OCA], [https://pdbe.org/7kbj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kbj RCSB], [https://www.ebi.ac.uk/pdbsum/7kbj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kbj ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GANAB_MOUSE GANAB_MOUSE] Cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER alpha-glucosidases (alpha-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER alpha-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER alpha-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four alpha-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses. | |||
N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum alpha-Glucosidases I and II with Antiviral Activity.,Karade SS, Hill ML, Kiappes JL, Manne R, Aakula B, Zitzmann N, Warfield KL, Treston AM, Mariuzza RA J Med Chem. 2021 Dec 23;64(24):18010-18024. doi: 10.1021/acs.jmedchem.1c01377. , Epub 2021 Dec 6. PMID:34870992<ref>PMID:34870992</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7kbj" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Alpha-glucosidase 3D structures|Alpha-glucosidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Karade SS]] | |||
[[Category: Mariuzza RA]] | |||
Latest revision as of 18:20, 18 October 2023
Co-crystal structure of alpha glucosidase with compound 9Co-crystal structure of alpha glucosidase with compound 9
Structural highlights
FunctionGANAB_MOUSE Cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins. Publication Abstract from PubMedMost enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER alpha-glucosidases (alpha-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER alpha-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER alpha-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four alpha-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses. N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum alpha-Glucosidases I and II with Antiviral Activity.,Karade SS, Hill ML, Kiappes JL, Manne R, Aakula B, Zitzmann N, Warfield KL, Treston AM, Mariuzza RA J Med Chem. 2021 Dec 23;64(24):18010-18024. doi: 10.1021/acs.jmedchem.1c01377. , Epub 2021 Dec 6. PMID:34870992[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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