PXD063860

PXD063860 is an original dataset announced via ProteomeXchange.

Title	Discovery of a novel binding mode for a histone deacetylase 6 inhibitor using PROTACs, computational and biochemical approaches.
Description	Abstract Histone deacetylase 6 (HDAC6) is primarily located in the cytoplasm and is responsible for deacetylating non-histone substrates, including α-tubulin, cortactin, and HSP90. HDAC6 possesses a unique structure with two catalytic domains (CD), each containing a catalytic zinc ion, and a zinc finger ubiquitin-binding domain. The structure-based design of HDAC6 inhibitors relies on the use of the zebrafish surrogate. Additionally, there are no reports of selective class IIb inhibitors lacking the zinc-binding group that targets the catalytic zinc ion. We have identified a novel, HDAC6 inhibitor named BAS-2. This inhibitor has a unique structure without an apparent zinc-binding group, and its binding mode is currently unknown. In this study, we employed a combined approach of structure-activity relationships (SAR), molecular modeling, mutational studies, and the application of novel Proteolysis Targeting Chimeras (PROTACs) technology to uncover the binding mode. Systematic variations indicated that BAS-2’s amide group was potentially in a solvent-exposed region. This observation was confirmed by the successful design of a PROTAC that induced HDAC6 degradation in a proteasomal dependent manner. Our findings revealed that BAS-2 did not inhibit the zebrafish surrogate HDAC6 enzyme. Using computational modelling we identified an essential role for aspartate 567 in HDAC6. This was then confirmed by mutational studies in cells, in the binding of BAS-2 to hHDAC6. This discovery opens up opportunities for pioneering the development of the next generation of HDAC6 inhibitors and degraders.
HostingRepository	PRIDE
AnnounceDate	2026-09-07
AnnouncementXML	Submission_2026-09-06_19:41:28.681.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Wynne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-12 11:26:10	ID requested
⏵ 1	2026-09-06 19:41:30	announced

10.1038/s41467-026-73146-5;

Rodrigues DA, Wang Y, Goulart Stollmaier J, Sullivan GP, D'Arcy C, Coughlan AY, Roe A, B, í, r, ó L, Watson PR, Osko JD, Twamley B, Wynne K, Cagney G, Bugly, ó P, Liu Y, Griffith DM, Christianson DW, Chonghaile TN, Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor. Nat Commun, 17(1):(2026) [pubmed]

submitter keyword: None

Dr Tríona
contact affiliation	Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland.
contact email	tnichonghaile@rcsi.com
lab head
Kieran Wynne
contact affiliation	University College Dublin
contact email	kieran.wynne1@ucd.ie
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/09/PXD063860

PRIDE project URI

• PRIDE
  1. PXD063860
     1. Label: PRIDE project
     2. Name: Discovery of a novel binding mode for a histone deacetylase 6 inhibitor using PROTACs, computational and biochemical approaches.