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==Structure of the Clostridium perfringens NagJ family 84 glycoside hydrolase, a homologue of human O-GlcNAcase in complex with PUGNAc== | |||
<StructureSection load='2cbj' size='340' side='right'caption='[[2cbj]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2cbj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_perfringens Clostridium perfringens]. The September 2011 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''O-GlcNAc Transferase'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2011_9 10.2210/rcsb_pdb/mom_2011_9]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CBJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CBJ 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]] 2.35Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=OAN:O-(2-ACETAMIDO-2-DEOXY+D-GLUCOPYRANOSYLIDENE)+AMINO-N-PHENYLCARBAMATE'>OAN</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=2cbj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cbj OCA], [https://pdbe.org/2cbj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cbj RCSB], [https://www.ebi.ac.uk/pdbsum/2cbj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cbj ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/OGA_CLOP1 OGA_CLOP1] Biological function unknown. Capable of hydrolyzing the glycosidic link of O-GlcNAcylated proteins. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cb/2cbj_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2cbj ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
O-linked N-acetylglucosamine (O-GlcNAc) modification of specific serines/threonines on intracellular proteins in higher eukaryotes has been shown to directly regulate important processes such as the cell cycle, insulin sensitivity and transcription. The structure, molecular mechanisms of catalysis, protein substrate recognition/specificity of the eukaryotic O-GlcNAc transferase and hydrolase are largely unknown. Here we describe the crystal structure, enzymology and in vitro activity on human substrates of Clostridium perfringens NagJ, a close homologue of human O-GlcNAcase (OGA), representing the first family 84 glycoside hydrolase structure. The structure reveals a deep active site pocket highly conserved with the human enzyme, compatible with binding of O-GlcNAcylated peptides. Together with mutagenesis data, the structure supports a variant of the substrate-assisted catalytic mechanism, involving two aspartic acids and an unusually positioned tyrosine. Insights into recognition of substrate come from a complex with the transition state mimic O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (Ki=5.4 nM). Strikingly, the enzyme is inhibited by the pseudosubstrate peptide Ala-Cys(-S-GlcNAc)-Ala, and has OGA activity against O-GlcNAcylated human proteins, suggesting that the enzyme is a suitable model for further studies into the function of human OGA. | |||
Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis.,Rao FV, Dorfmueller HC, Villa F, Allwood M, Eggleston IM, van Aalten DM EMBO J. 2006 Apr 5;25(7):1569-78. Epub 2006 Mar 16. PMID:16541109<ref>PMID:16541109</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2cbj" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Hyaluronidase 3D structures|Hyaluronidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Clostridium perfringens]] | [[Category: Clostridium perfringens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: O-GlcNAc Transferase]] | ||
[[Category: | [[Category: RCSB PDB Molecule of the Month]] | ||
[[Category: Allwood | [[Category: Allwood M]] | ||
[[Category: Dorfmueller | [[Category: Dorfmueller HC]] | ||
[[Category: Eggleston | [[Category: Eggleston IM]] | ||
[[Category: Rao | [[Category: Rao FV]] | ||
[[Category: Villa | [[Category: Villa F]] | ||
[[Category: | [[Category: Van Aalten DMF]] | ||
Latest revision as of 17:11, 13 December 2023
Structure of the Clostridium perfringens NagJ family 84 glycoside hydrolase, a homologue of human O-GlcNAcase in complex with PUGNAcStructure of the Clostridium perfringens NagJ family 84 glycoside hydrolase, a homologue of human O-GlcNAcase in complex with PUGNAc
Structural highlights
FunctionOGA_CLOP1 Biological function unknown. Capable of hydrolyzing the glycosidic link of O-GlcNAcylated proteins. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedO-linked N-acetylglucosamine (O-GlcNAc) modification of specific serines/threonines on intracellular proteins in higher eukaryotes has been shown to directly regulate important processes such as the cell cycle, insulin sensitivity and transcription. The structure, molecular mechanisms of catalysis, protein substrate recognition/specificity of the eukaryotic O-GlcNAc transferase and hydrolase are largely unknown. Here we describe the crystal structure, enzymology and in vitro activity on human substrates of Clostridium perfringens NagJ, a close homologue of human O-GlcNAcase (OGA), representing the first family 84 glycoside hydrolase structure. The structure reveals a deep active site pocket highly conserved with the human enzyme, compatible with binding of O-GlcNAcylated peptides. Together with mutagenesis data, the structure supports a variant of the substrate-assisted catalytic mechanism, involving two aspartic acids and an unusually positioned tyrosine. Insights into recognition of substrate come from a complex with the transition state mimic O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (Ki=5.4 nM). Strikingly, the enzyme is inhibited by the pseudosubstrate peptide Ala-Cys(-S-GlcNAc)-Ala, and has OGA activity against O-GlcNAcylated human proteins, suggesting that the enzyme is a suitable model for further studies into the function of human OGA. Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis.,Rao FV, Dorfmueller HC, Villa F, Allwood M, Eggleston IM, van Aalten DM EMBO J. 2006 Apr 5;25(7):1569-78. Epub 2006 Mar 16. PMID:16541109[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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