6AFD

DJ-1 with compound 6

Summary for 6AFD

• Entry DOI: 10.2210/pdb6afd/pdb
• Descriptor: Protein/nucleic acid deglycase DJ-1, 7-methyl-1~{H}-indole-2,3-dione, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: dj-1, parkinson's disease, drug discovery, fragment-based drug discovery, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20274.82

Authors

Caaveiro, J.M.M.,Tashiro, S.,Tsumoto, K. (deposition date: 2018-08-08, release date: 2018-08-29, Last modification date: 2023-11-22)

Primary citation

Tashiro, S.,Caaveiro, J.M.M.,Nakakido, M.,Tanabe, A.,Nagatoishi, S.,Tamura, Y.,Matsuda, N.,Liu, D.,Hoang, Q.Q.,Tsumoto, K.
Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1.
ACS Chem. Biol., 13:2783-2793, 2018

PubMed Abstract: DJ-1 is a Parkinson's disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.

PubMed: 30063823
DOI: 10.1021/acschembio.8b00701

Experimental method

X-RAY DIFFRACTION (1.48 Å)