5WPB

Crystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxalin-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain

Summary for 5WPB

• Entry DOI: 10.2210/pdb5wpb/pdb
• Descriptor: Histone deacetylase 6, ZINC ION, 3-{3-[(pyridin-2-yl)methoxy]quinoxalin-2-yl}propanoic acid, ... (5 entities in total)
• Functional Keywords: histone deacetylase, hdac, hdac6, fragment screening, structural genomics consortium, sgc, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 12133.75

Authors

Harding, R.J.,Tempel, W.,Ferreira de Freitas, R.,Franzoni, I.,Ravichandran, M.,Lautens, M.,Santhakumar, V.,Schapira, M.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Structural Genomics Consortium (SGC) (deposition date: 2017-08-04, release date: 2017-08-23, Last modification date: 2024-03-13)

Primary citation

Harding, R.J.,Ferreira de Freitas, R.,Collins, P.,Franzoni, I.,Ravichandran, M.,Ouyang, H.,Juarez-Ornelas, K.A.,Lautens, M.,Schapira, M.,von Delft, F.,Santhakumar, V.,Arrowsmith, C.H.
Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin.
J. Med. Chem., 60:9090-9096, 2017

PubMed Abstract: Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.

PubMed: 29019676
DOI: 10.1021/acs.jmedchem.7b00933

Experimental method

X-RAY DIFFRACTION (1.55 Å)