43EA

Crystal structure of Aspergillus fumigatus histone deacetylase Hos3 in complex with T2383

Summary for 43EA

• Entry DOI: 10.2210/pdb43ea/pdb
• Descriptor: Histone deacetylase HosB, Panobinostat, ZINC ION, ... (5 entities in total)
• Functional Keywords: stone deacetylase, fungal hdac, zinc-dependent enzyme, t2383, gene regulation
• Biological source: Aspergillus fumigatus (strain CBS 144.89 / FGSC A1163 / CEA10)
• Total number of polymer chains: 1
• Total formula weight: 65499.79

Authors

Yang, H.W.,Li, T.,Liu, C.T.,Wang, X.D.,Li, T.,Yang, N. (deposition date: 2026-06-27, release date: 2026-10-28)

Primary citation

Yang, H.,Li, T.,Liu, C.,Wang, X.,Li, T.,Yang, N.
Structural and mechanistic basis of selective inhibition of the fungal-specific histone deacetylase Hos3 from the pathogenic fungus Aspergillus fumigatus.
Protein Sci., 35:e70827-e70827, 2026

PubMed Abstract: Histone deacetylases (HDACs) are critical epigenetic regulators of fungal growth and pathogenicity and constitute promising targets for antifungal drug development. Hos3 defines a fungal-specific HDAC subclass that lacks a clear mammalian ortholog; however, the structural determinants underlying its selective inhibition remain poorly characterized. Here, we integrated x-ray crystallography with biochemical and biophysical analyses to comprehensively characterize the catalytic properties of Hos3 from the pathogenic fungus Aspergillus fumigatus (AfHos3) and its inhibition by the hydroxamate-based compound T2383. Despite high conservation of catalytic residues, AfHos3 displayed significantly higher intrinsic catalytic activity and markedly enhanced sensitivity to T2383 compared with its yeast homolog ScHos3. The crystal structure of the AfHos3-T2383 complex revealed a canonical zinc-dependent inhibitor-binding mode, coupled with a distinct, fungal-specific architecture of the substrate and inhibitor binding pocket. Structural and functional studies identified an aromatic clamp, comprising residues F371 and F443, that is indispensable for both catalytic activity and ligand stabilization. Furthermore, fungal-specific residues M538 and V205, together with structural elements loopA and α12, shape the catalytic-pocket environment and differentially influence enzymatic activity and T2383 responsiveness. Notably, the dimeric assembly of AfHos3 was associated with optimal enzymatic activity but did not influence inhibitor recognition. Collectively, these findings elucidate how fungal-specific structural elements synergize with the evolutionarily conserved catalytic core to govern selective inhibitor recognition, providing a robust structural and mechanistic framework for the rational design of fungal-selective HDAC inhibitors.

PubMed: 42876389
DOI: 10.1002/pro.70827

Experimental method

X-RAY DIFFRACTION (1.98 Å)