Zinc cofactor in human histone deacetylase 8: Requirement for function and opportunity for drug discovery

Garcia-Franco, Paula M. ; Falcó-Martí, F. Javier (Universidad de Zaragoza) ; Jeblaoui, Hajar ; Asencio del Rio, Marta ; Ortega-Alarcon, David ; Vega, Sonia ; Galano-Frutos, Juan J. ; Abian, Olga (Universidad de Zaragoza) ; Velazquez-Campoy, Adrian (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.ijbiomac.2025.149851

Año: 2026

Publicado en: International journal of biological macromolecules 339, 26 (2026), 149851 [16 pp.]
ISSN: 0141-8130

Financiación: info:eu-repo/grantAgreement/ES/DGA/B08-24R
Financiación: info:eu-repo/grantAgreement/ES/DGA/B25-23R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-23R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-ERDF-ESF/PI21-00394
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/i-PFIS-IFI23-00020
Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739
Financiación: info:eu-repo/grantAgreement/ES/MCIU/PID2024-160408OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN-AEI/PRTR-C17.I1
Financiación: info:eu-repo/grantAgreement/ES/MICIU/JDC2023-052992-I

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)