6TCY

X-ray structure of Danio rerio histone deacetylase 6 (HDAC6) CD2 in complex with a inhibitor SS555

This is a non-PDB format compatible entry.

Summary for 6TCY

• Entry DOI: 10.2210/pdb6tcy/pdb
• Descriptor: Histone deacetylase 6, DIMETHYL SULFOXIDE, ZINC ION, ... (11 entities in total)
• Functional Keywords: protein deacetylase, histone deacetylase 6, zinc-binding, isoxazole-2 3-hydroxamate analogues, hydrolase
• Biological source: Danio rerio (Zebrafish)
• Total number of polymer chains: 2
• Total formula weight: 81738.80

Authors

Stransky, J.,Barinka, C. (deposition date: 2019-11-06, release date: 2020-11-04, Last modification date: 2024-01-24)

Primary citation

Noonepalle, S.,Shen, S.,Ptacek, J.,Tavares, M.T.,Zhang, G.,Stransky, J.,Pavlicek, J.,Ferreira, G.M.,Hadley, M.,Pelaez, G.,Barinka, C.,Kozikowski, A.P.,Villagra, A.
Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models.
J.Med.Chem., 63:10246-10262, 2020

PubMed Abstract: Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

PubMed: 32815366
DOI: 10.1021/acs.jmedchem.0c00567

Experimental method

X-RAY DIFFRACTION (1.6 Å)