6CEF

Crystal structure of fragment 3-(1,3-Benzothiazol-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain

Summary for 6CEF

• Entry DOI: 10.2210/pdb6cef/pdb
• Descriptor: Histone deacetylase 6, ZINC ION, UNKNOWN ATOM OR ION, ... (5 entities in total)
• Functional Keywords: histone deacetylase, hdac, hdac6, ubiquitin, structural genomics consortium, sgc, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: Q9UBN7
• Total number of polymer chains: 1
• Total formula weight: 12336.08

Authors

Harding, R.J.,Halabelian, L.,Ferreira de Freitas, R.,Ravichandran, M.,Santhakumar, V.,Schapira, M.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.M.,Structural Genomics Consortium (SGC) (deposition date: 2018-02-11, release date: 2018-02-28, Last modification date: 2023-10-04)

Primary citation

Ferreira de Freitas, R.,Harding, R.J.,Franzoni, I.,Ravichandran, M.,Mann, M.K.,Ouyang, H.,Lautens, M.,Santhakumar, V.,Arrowsmith, C.H.,Schapira, M.
Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.
J. Med. Chem., 61:4517-4527, 2018

PubMed Abstract: HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

PubMed: 29741882
DOI: 10.1021/acs.jmedchem.8b00258

Experimental method

X-RAY DIFFRACTION (1.8 Å)