biostudies-literatureLuo YNatural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)National Natural Science Foundation of China (National Science Foundation of China)221https://www.ebi.ac.uk/biostudies/studies/S-EPMC11821889biostudies-literatureUnknown8(1)Histone deacetylase 8 (HDAC8) is a well-known epigenetic regulator for cancer therapy. However, developing targeted inhibitors for HDAC8 is challenging due to a limited understanding of its structural dynamics, which is crucial for ligand interaction. Here, we employed an integrated approach, including native mass spectrometry (native MS), hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics (MD) simulation, to investigate the inhibition mechanism and dynamic regulation of human HDAC8 (hHDAC8) by selective inhibitor PCI-34051, compared with the pan-inhibitor SAHA. Our results revealed that PCI-34051 engages with an expanded set of residues and conforms more aptly to the binding channel of hHDAC8, stabilizing the flexible loops surrounding the binding channel. MoreCommunications biologyBinding mechanism and distant regulation of histone deacetylase 8 by PCI-34051.PMC11821889818728362019A15150112652022A151501096591953102Qiu YLi HYan ZZhang YChu XLuo YfalseBinding mechanism and distant regulation of histone deacetylase 8 by PCI-34051.Histone deacetylase 8 (HDAC8) is a well-known epigenetic regulator for cancer therapy. However, developing targeted inhibitors for HDAC8 is challenging due to a limited understanding of its structural dynamics, which is crucial for ligand interaction. Here, we employed an integrated approach, including native mass spectrometry (native MS), hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics (MD) simulation, to investigate the inhibition mechanism and dynamic regulation of human HDAC8 (hHDAC8) by selective inhibitor PCI-34051, compared with the pan-inhibitor SAHA. Our results revealed that PCI-34051 engages with an expanded set of residues and conforms more aptly to the binding channel of hHDAC8, stabilizing the flexible loops surrounding the binding channel. More2025-01-01T00:00:00Z2025 Feb2026-06-01T08:47:55.511Z2025-04-07T11:26:55.436ZS-EPMC118218893993981410.1038/s42003-025-07649-0