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| | <StructureSection load='6tdg' size='340' side='right'caption='[[6tdg]], [[Resolution|resolution]] 1.74Å' scene=''> | | <StructureSection load='6tdg' size='340' side='right'caption='[[6tdg]], [[Resolution|resolution]] 1.74Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tdg]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspfu Aspfu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TDG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TDG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tdg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus_Af293 Aspergillus fumigatus Af293]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TDG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TDG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACO:ACETYL+COENZYME+*A'>ACO</scene>, <scene name='pdbligand=N3W:2-chloranyl-3-(4~{H}-1,2,4-triazol-3-yl)aniline'>N3W</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.74Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AFUA_6G02460 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=330879 ASPFU])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACO:ACETYL+COENZYME+*A'>ACO</scene>, <scene name='pdbligand=N3W:2-chloranyl-3-(4~{H}-1,2,4-triazol-3-yl)aniline'>N3W</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucosamine-phosphate_N-acetyltransferase Glucosamine-phosphate N-acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.4 2.3.1.4] </span></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=6tdg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tdg OCA], [https://pdbe.org/6tdg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tdg RCSB], [https://www.ebi.ac.uk/pdbsum/6tdg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tdg ProSAT]</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=6tdg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tdg OCA], [http://pdbe.org/6tdg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tdg RCSB], [http://www.ebi.ac.uk/pdbsum/6tdg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tdg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q4WCU5_ASPFU Q4WCU5_ASPFU] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aspfu]] | + | [[Category: Aspergillus fumigatus Af293]] |
| - | [[Category: Glucosamine-phosphate N-acetyltransferase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lockhart, D]] | + | [[Category: Lockhart D]] |
| - | [[Category: Raimi, O G]] | + | [[Category: Raimi OG]] |
| - | [[Category: Stanley, M]] | + | [[Category: Stanley M]] |
| - | [[Category: Anti fungal]]
| + | |
| - | [[Category: Aspergillus fumigatus]]
| + | |
| - | [[Category: Fragment screening]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
Q4WCU5_ASPFU
Publication Abstract from PubMed
Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment, including host defense responses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. Because this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Deltagna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective sub-micromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus.
Targeting a critical step in fungal hexosamine biosynthesis.,Lockhart DEA, Stanley M, Raimi OG, Robinson DA, Boldovjakova D, Squair DR, Ferenbach AT, Fang W, van Aalten DMF J Biol Chem. 2020 Apr 27. pii: RA120.012985. doi: 10.1074/jbc.RA120.012985. PMID:32341126[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lockhart DEA, Stanley M, Raimi OG, Robinson DA, Boldovjakova D, Squair DR, Ferenbach AT, Fang W, van Aalten DMF. Targeting a critical step in fungal hexosamine biosynthesis. J Biol Chem. 2020 Apr 27. pii: RA120.012985. doi: 10.1074/jbc.RA120.012985. PMID:32341126 doi:http://dx.doi.org/10.1074/jbc.RA120.012985
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