PDBsum entry 6afb

Hydrolase

PDB id: 6afb

Contents

Protein chain

187 a.a.

Ligands

ISN ×2

DMS

Metals

_CL

Waters ×210

PDB id:

6afb

Name:

Hydrolase

Title:

Dj-1 c106s incubated with isatin

Structure:

Protein/nucleic acid deglycase dj-1. Chain: a. Synonym: maillard deglycase,oncogene dj1,parkinson disease protein 7, parkinsonism-associated deglycase,protein dj-1,dj-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: park7. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

1.60Å R-factor: 0.146 R-free: 0.172

Authors:

J.M.M.Caaveiro,S.Tashiro,K.Tsumoto

Key ref:

S.Tashiro et al. (2018). Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1. ACS Chem Biol, 13, 2783-2793. PubMed id: 30063823 DOI: 10.1021/acschembio.8b00701

Date:

08-Aug-18 Release date: 29-Aug-18

Protein chain

Q99497  (PARK7_HUMAN) -  Parkinson disease protein 7 from Homo sapiens

Seq: 189 a.a.

Struc: 187 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: E.C.3.1.2.- - ?????
• Enzyme class 3: E.C.3.5.1.- - ?????
• Enzyme class 4: E.C.3.5.1.124 - protein deglycase.
• Reaction:
  1. N(omega)-(1-hydroxy-2-oxopropyl)-L-arginyl-[protein] + H2O = lactate + L-arginyl-[protein] + H⁺
  2. N₆-(1-hydroxy-2-oxopropyl)-L-lysyl-[protein] + H2O = lactate + L-lysyl-[protein] + H⁺
  3. S-(1-hydroxy-2-oxopropyl)-L-cysteinyl-[protein] + H2O = lactate + L-cysteinyl-[protein] + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acschembio.8b00701

ACS Chem Biol 13:2783-2793 (2018)

PubMed id: 30063823

Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1.

S.Tashiro, J.M.M.Caaveiro, M.Nakakido, A.Tanabe, S.Nagatoishi, Y.Tamura, N.Matsuda, D.Liu, Q.Q.Hoang, K.Tsumoto.

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.