{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T08:47:47Z","timestamp":1792054067128,"version":"4.4.0"},"reference-count":37,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370731"],"award-info":[{"award-number":["32370731"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Histone deacetylases (HDACs) are critical epigenetic regulators of fungal growth and pathogenicity and constitute promising targets for antifungal drug development. Hos3 defines a fungal\u2010specific HDAC subclass that lacks a clear mammalian ortholog; however, the structural determinants underlying its selective inhibition remain poorly characterized. Here, we integrated x\u2010ray crystallography with biochemical and biophysical analyses to comprehensively characterize the catalytic properties of Hos3 from the pathogenic fungus\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    (\n                    <jats:italic>Af<\/jats:italic>\n                    Hos3) and its inhibition by the hydroxamate\u2010based compound T2383. Despite high conservation of catalytic residues,\n                    <jats:italic>Af<\/jats:italic>\n                    Hos3 displayed significantly higher intrinsic catalytic activity and markedly enhanced sensitivity to T2383 compared with its yeast homolog\n                    <jats:italic>Sc<\/jats:italic>\n                    Hos3. The crystal structure of the\n                    <jats:italic>Af<\/jats:italic>\n                    Hos3\u2013T2383 complex revealed a canonical zinc\u2010dependent inhibitor\u2010binding mode, coupled with a distinct, fungal\u2010specific 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\u2010specific residues M538 and V205, together with structural elements loopA and\n                    <jats:italic>\u03b1<\/jats:italic>\n                    12, shape the catalytic\u2010pocket environment and differentially influence enzymatic activity and T2383 responsiveness. Notably, the dimeric assembly of\n                    <jats:italic>Af<\/jats:italic>\n                    Hos3 was associated with optimal enzymatic activity but did not influence inhibitor recognition. Collectively, these findings elucidate how fungal\u2010specific 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\u2010selective HDAC inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/pro.70827","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T08:18:13Z","timestamp":1792052293000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural and mechanistic basis of selective inhibition of the fungal\u2010specific histone deacetylase Hos3 from the pathogenic fungus\n                    <scp>\n                      <i>Aspergillus fumigatus<\/i>\n                    <\/scp>"],"prefix":"10.1002","volume":"35","author":[{"given":"Hongwu","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuantong","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-6630","authenticated-orcid":false,"given":"Na","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University  Tianjin China"},{"name":"Laboratory of Pathogen Microbiology and Immunology, Beijing Key Laboratory of Antimicrobial\u2010Resistant Pathogen Microbiology and Al\u2010Empowered Containment, Institute of Microbiology, Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"issue":"8016","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of 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