5oa7
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Fe(II)/(alpha)ketoglutarate-dependent dioxygenase AsqJ_V72I mutant in complex with cyclopeptin (1b)== | |
| + | <StructureSection load='5oa7' size='340' side='right'caption='[[5oa7]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5oa7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_nidulans_FGSC_A4 Aspergillus nidulans FGSC A4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OA7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OA7 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]] 1.65Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58K:CYCLOPEPTIN'>58K</scene>, <scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=5oa7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oa7 OCA], [https://pdbe.org/5oa7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5oa7 RCSB], [https://www.ebi.ac.uk/pdbsum/5oa7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5oa7 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/ASQJ_EMENI ASQJ_EMENI] Iron/alpha-ketoglutarate-dependent dioxygenase; part of the gene cluster that mediates the biosynthesis of the aspoquinolone mycotoxins (PubMed:25251934, PubMed:26553478). The first stage is catalyzed by the nonribosomal pepdide synthetase asqK that condenses anthranilic acid and O-methyl-L-tyrosine to produce 4'-methoxycyclopeptin (PubMed:25251934). AsqK is also able to use anthranilic acid and L-phenylalanine as substrates to produce cyclopeptin, but at a tenfold lower rate (PubMed:25251934). 4'-methoxycyclopeptin is then converted to 4'-methoxydehydrocyclopeptin by the ketoglutarate-dependent dioxygenase asqJ through dehydrogenation to form a double bond between C-alpha and C-beta of the O-methyltyrosine side chain (PubMed:25251934, PubMed:26553478). AsqJ also converts its first product 4'-methoxydehydrocyclopeptin to 4'-methoxycyclopenin (PubMed:25251934). AsqJ is a very unique dioxygenase which is capable of catalyzing radical-mediated dehydrogenation and epoxidation reactions sequentially on a 6,7-benzo-diazepinedione substrate in the 4'-methoxyviridicatin biosynthetic pathway (PubMed:25251934). The following conversion of 4'-methoxycyclopenin into 4'-methoxyviridicatin proceeds non-enzymatically (PubMed:25251934). AsqJ is also capable of converting cyclopeptin into dehydrocyclopeptin and cyclopenin in a sequential fashion (PubMed:25251934). Cyclopenin can be converted into viridicatin non-enzymatically (PubMed:25251934). 4'-methoxyviridicatin likely acts as a precursor of quinolone natural products, such as aspoquinolones, peniprequinolones, penigequinolones, and yaequinolones (PubMed:25251934). Further characterization of the remaining genes in the cluster has still to be done to determine the exact identity of quinolone products this cluster is responsible for biosynthesizing (PubMed:25251934).<ref>PMID:25251934</ref> <ref>PMID:26553478</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The recently discovered Fe(II)/alpha-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans stereoselectively catalyzes a multistep synthesis of quinolone alkaloids, natural products with significant biomedical applications. To probe molecular mechanisms of this elusive catalytic process, we combine here multi-scale quantum and classical molecular simulations with X-ray crystallography, and in vitro biochemical activity studies. We discover that methylation of the substrate is essential for the activity of AsqJ, establishing molecular strain that fine-tunes pi-stacking interactions within the active site. To rationally engineer AsqJ for modified substrates, we amplify dispersive interactions within the active site. We demonstrate that the engineered enzyme has a drastically enhanced catalytic activity for non-methylated surrogates, confirming our computational data and resolved high-resolution X-ray structures at 1.55 A resolution. Our combined findings provide crucial mechanistic understanding of the function of AsqJ and showcase how combination of computational and experimental data enables to rationally engineer enzymes. | ||
| - | + | Catalytic mechanism and molecular engineering of quinolone biosynthesis in dioxygenase AsqJ.,Mader SL, Brauer A, Groll M, Kaila VRI Nat Commun. 2018 Mar 21;9(1):1168. doi: 10.1038/s41467-018-03442-2. PMID:29563492<ref>PMID:29563492</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 5oa7" style="background-color:#fffaf0;"></div> |
| - | [[Category: Groll | + | |
| - | [[Category: | + | ==See Also== |
| + | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Aspergillus nidulans FGSC A4]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Braeuer A]] | ||
| + | [[Category: Groll M]] | ||
| + | [[Category: Kaila VRI]] | ||
Current revision
Fe(II)/(alpha)ketoglutarate-dependent dioxygenase AsqJ_V72I mutant in complex with cyclopeptin (1b)
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