9yjz: Difference between revisions
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==cryoEM structure of Apo Aspergillus fumigatus acetolactate synthase (ALS)== | |||
<StructureSection load='9yjz' size='340' side='right'caption='[[9yjz]], [[Resolution|resolution]] 2.76Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9yjz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9YJZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9YJZ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.76Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPP:THIAMINE+DIPHOSPHATE'>TPP</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=9yjz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9yjz OCA], [https://pdbe.org/9yjz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9yjz RCSB], [https://www.ebi.ac.uk/pdbsum/9yjz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9yjz ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in Aspergillus terreus encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that 1 surpasses existing ALS inhibitors in efficacy against Aspergillus fumigatus and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 1 and ALS, distinct from known inhibitors, and finally, we demonstrate that ALS is essential for virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery. | |||
An Antifungal with a Novel Mechanism of Action Discovered via Resistance Gene-Guided Genome Mining.,Perlatti B, Vellanki S, Zhang Y, Chiang YM, Hu Y, Yuan M, Dunbar K, Fine A, Grau MF, Li S, O'Donnell T, Shenoy R, Li H, Shi H, Xu X, Chen Z, Arvedson T, Tang Y, Cramer RA, Cee V, Harvey CJB ACS Cent Sci. 2026 Jan 31;12(2):197-207. doi: 10.1021/acscentsci.5c02019. , eCollection 2026 Feb 25. PMID:41768770<ref>PMID:41768770</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9yjz" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Aspergillus fumigatus]] | |||
[[Category: Large Structures]] | |||
[[Category: Hu Y]] | |||
