168249 20260130124311.0 doi 10.1016/j.ijbiomac.2025.149851 sideral 147764 ART-2026-147764 eng Garcia-Franco, Paula M. Zinc cofactor in human histone deacetylase 8: Requirement for function and opportunity for drug discovery 2026 HDAC8 (histone deacetylase 8), a class I HDAC, is a promising target for different disorders: X-linked intellectual disability, fibrotic disease, cancer, and several neuropathological diseases. The structural and functional similarity between HDACs hinders the development of selective HDAC8 inhibitors. To date, no drugs based on competitive inhibition have been approved. In order to identify weaknesses in HDAC8 amenable to drug discovery, we report here a comprehensive thermodynamic characterization of the structural stability and its modulation by the interaction with its zinc (Zn2+) cofactor using a combination of experimental and computational techniques. HDAC8 represents an interesting example of an allosteric protein in the broad sense, in which its cofactor, the zinc ion, modulates its conformational equilibrium. The native, inactive, zinc-free state is physiologically relevant considering that the intracellular concentration of zinc is very low and may constitute a valid target for drug discovery. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/DGA/B08-24R info:eu-repo/grantAgreement/ES/DGA/B25-23R info:eu-repo/grantAgreement/ES/DGA/E45-23R info:eu-repo/grantAgreement/ES/ISCIII-ERDF-ESF/PI21-00394 info:eu-repo/grantAgreement/ES/ISCIII/i-PFIS-IFI23-00020 info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739 info:eu-repo/grantAgreement/ES/MCIU/PID2024-160408OB-I00 info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00 info:eu-repo/grantAgreement/ES/MICINN-AEI/PRTR-C17.I1 info:eu-repo/grantAgreement/ES/MICIU/JDC2023-052992-I info:eu-repo/semantics/openAccess by-nc-nd https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Falcó-Martí, F. Javier Universidad de Zaragoza Jeblaoui, Hajar Asencio del Rio, Marta Ortega-Alarcon, David (orcid)0000-0003-1885-4365 Vega, Sonia (orcid)0000-0002-1232-6310 Galano-Frutos, Juan J. (orcid)0000-0002-1896-7805 Abian, Olga Universidad de Zaragoza (orcid)0000-0001-5664-1729 Velazquez-Campoy, Adrian Universidad de Zaragoza (orcid)0000-0001-5702-4538 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 339, 26 (2026), 149851 [16 pp.] Int. j. biol. macromol. International journal of biological macromolecules 0141-8130 3009551 http://zaguan.unizar.es/record/168249/files/texto_completo.pdf Versión publicada 2596892 http://zaguan.unizar.es/record/168249/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:168249 articulos driver 2026-01-30-12:20:44 ARTICLE