6CEE
Crystal structure of fragment 3-(1-Methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)propionic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain
Summary for 6CEE
| Entry DOI | 10.2210/pdb6cee/pdb |
| Descriptor | Histone deacetylase 6, ZINC ION, 3-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)propanoic acid, ... (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 | 12361.07 |
| Authors | Harding, R.J.,Halabelian, L.,Ferreira de Freitas, R.,Franzoni, I.,Ravichandran, M.,Lautens, 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 Cited by 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: 29741882DOI: 10.1021/acs.jmedchem.8b00258 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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