7ZYU

HDAC6 ZnF domain inhibitor - DARPin (Designed Ankyrin repeat protein) F10

Replaces:  7ATT

Summary for 7ZYU

• Entry DOI: 10.2210/pdb7zyu/pdb
• Descriptor: Histone deacetylase 6, Designed Ankyrin repeat protein F10, ZINC ION, ... (5 entities in total)
• Functional Keywords: darpin, zinc finger, de novo protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 29833.94

Authors

Wang, L.,Kempf, G. (deposition date: 2022-05-25, release date: 2022-06-01, Last modification date: 2024-10-09)

Primary citation

Wang, L.,Moreira, E.A.,Kempf, G.,Miyake, Y.,Oliveira Esteves, B.I.,Fahmi, A.,Schaefer, J.V.,Dreier, B.,Yamauchi, Y.,Alves, M.P.,Pluckthun, A.,Matthias, P.
Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways.
Cell Rep, 39:110736-110736, 2022

PubMed Abstract: The deacetylase HDAC6 has tandem catalytic domains and a zinc finger domain (ZnF) binding ubiquitin (Ub). While the catalytic domain has an antiviral effect, the ZnF facilitates influenza A virus (IAV) infection and cellular stress responses. By recruiting Ub via the ZnF, HDAC6 promotes the formation of aggresomes and stress granules (SGs), dynamic structures associated with pathologies such as neurodegeneration. IAV subverts the aggresome/HDAC6 pathway to facilitate capsid uncoating during early infection. To target this pathway, we generate designed ankyrin repeat proteins (DARPins) binding the ZnF; one of these prevents interaction with Ub in vitro and in cells. Crystallographic analysis shows that it blocks the ZnF pocket where Ub engages. Conditional expression of this DARPin reversibly impairs infection by IAV and Zika virus; moreover, SGs and aggresomes are downregulated. These results validate the HDAC6 ZnF as an attractive target for drug discovery.

PubMed: 35476995
DOI: 10.1016/j.celrep.2022.110736

Experimental method

X-RAY DIFFRACTION (2.43 Å)