9YK0
cryoEM structure of Aspergillus fumigatus acetolactate synthase (ALS) in complex with a novel inhibitor
This is a non-PDB format compatible entry.
Summary for 9YK0
| Entry DOI | 10.2210/pdb9yk0/pdb |
| EMDB information | 73041 |
| Descriptor | Acetolactate synthase, MAGNESIUM ION, THIAMINE DIPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | antifungal target, herbicide target, anti fugal infection, natural product, plant protein |
| Biological source | Aspergillus fumigatus |
| Total number of polymer chains | 2 |
| Total formula weight | 143865.02 |
| Authors | |
| Primary citation | Perlatti, B.,Vellanki, S.,Zhang, Y.,Chiang, Y.M.,Hu, Y.,Yuan, M.,Dunbar, K.,Fine, A.,Grau, M.F.,Li, S.,O'Donnell, T.,Shenoy, R.,Li, H.,Shi, H.,Xu, X.,Chen, Z.,Arvedson, T.,Tang, Y.,Cramer, R.A.,Cee, V.,Harvey, C.J.B. An Antifungal with a Novel Mechanism of Action Discovered via Resistance Gene-Guided Genome Mining. Acs Cent.Sci., 12:197-207, 2026 Cited by PubMed Abstract: 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 encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that surpasses existing ALS inhibitors in efficacy against and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 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. PubMed: 41768770DOI: 10.1021/acscentsci.5c02019 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.36 Å) |
Structure validation
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