Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD.
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Electrostatic interactions between middle domain motif-1 and the AAA1 module of the bacterial ClpB chaperone are essential for protein disaggregation.
J Biol Chem
December 2018
From the Department of Biology, Faculty of Science and Engineering and
ClpB, a bacterial homologue of heat shock protein 104 (Hsp104), can disentangle aggregated proteins with the help of the DnaK, a bacterial Hsp70, and its co-factors. As a member of the expanded superfamily of ATPases associated with diverse cellular activities (AAA), ClpB forms a hexameric ring structure, with each protomer containing two AAA modules, AAA1 and AAA2. A long coiled-coil middle domain (MD) is present in the C-terminal region of the AAA1 and surrounds the main body of the ring.
View Article and Find Full Text PDFStructural determinants for protein unfolding and translocation by the Hsp104 protein disaggregase.
Biosci Rep
December 2017
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, U.S.A.
Article Synopsis
- *Key to Hsp104's function are specific amino acid loops in its ATP-binding domains that play crucial roles in substrate translocation and interaction.
- *Research shows that both flanking aliphatic residues and loop-2 are vital for Hsp104's activity; mutations can significantly impair its function in disaggregating proteins.
Mutant Analysis Reveals Allosteric Regulation of ClpB Disaggregase.
Front Mol Biosci
February 2017
Center for Molecular Biology of the Heidelberg University, German Cancer Research Center Heidelberg, Germany.
The members of the hexameric AAA+ disaggregase of and , ClpB, and Hsp104, cooperate with the Hsp70 chaperone system in the solubilization of aggregated proteins. Aggregate solubilization relies on a substrate threading activity of ClpB/Hsp104 fueled by ATP hydrolysis in both ATPase rings (AAA-1, AAA-2). ClpB/Hsp104 ATPase activity is controlled by the M-domains, which associate to the AAA-1 ring to downregulate ATP hydrolysis.
View Article and Find Full Text PDFAnalysis of the cooperative ATPase cycle of the AAA+ chaperone ClpB from Thermus thermophilus by using ordered heterohexamers with an alternating subunit arrangement.
J Biol Chem
April 2015
From the Department of Biology, Faculty of Science and Engineering and the Institute for Integrative Neurobiology, Konan University, Okamoto 8-9-1, Kobe 658-8501, Japan
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Roles of conserved arginines in ATP-binding domains of AAA+ chaperone ClpB from Thermus thermophilus.
FEBS J
July 2011
Department of Biology, Faculty of Science and Engineering, Konan University, Okamoto, Kobe, Japan.
ClpB, a member of the expanded superfamily of ATPases associated with diverse cellular activities (AAA+), forms a ring-shaped hexamer and cooperates with the DnaK chaperone system to reactivate aggregated proteins in an ATP-dependent manner. The ClpB protomer consists of an N-terminal domain, an AAA+ module (AAA-1), a middle domain, and a second AAA+ module (AAA-2). Each AAA+ module contains highly conserved WalkerA and WalkerB motifs, and two arginines (AAA-1) or one arginine (AAA-2).
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