View source for 6tdh


==Crystal structure of Aspergillus fumigatus Glucosamine-6-phosphate N-acetyltransferase 1 in complex with compound 1==
<StructureSection load='6tdh' size='340' side='right'caption='[[6tdh]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6tdh]] 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=6TDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TDH 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]] 1.58&#8491;</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=N2Z:3-(2-chlorophenyl)-4~{H}-1,2,4-triazole'>N2Z</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=6tdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tdh OCA], [https://pdbe.org/6tdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tdh RCSB], [https://www.ebi.ac.uk/pdbsum/6tdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tdh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q4WCU5_ASPFU Q4WCU5_ASPFU] 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:32341126</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6tdh" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Aspergillus fumigatus Af293]]
[[Category: Large Structures]]
[[Category: Lockhart D]]
[[Category: Raimi OG]]
[[Category: Stanley M]]