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AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

Zhang, Gang and Li, Shan and Cheng, Kai-Wen and Chou, Tsui-Fen (2021) AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors. European Journal of Medicinal Chemistry, 219 . Art. No. 113446. ISSN 0223-5234. doi:10.1016/j.ejmech.2021.113446. https://resolver.caltech.edu/CaltechAUTHORS:20210413-071559531

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Abstract

ATPases Associated with Diverse Cellular Activity (AAA ATPase) are essential enzymes found in all organisms. They are involved in various processes such as DNA replication, protein degradation, membrane fusion, microtubule serving, peroxisome biogenesis, signal transduction, and the regulation of gene expression. Due to the importance of AAA ATPases, several researchers identified and developed small-molecule inhibitors against these enzymes. We discuss six AAA ATPases that are potential drug targets and have well-developed inhibitors. We compare available structures that suggest significant differences of the ATP binding pockets among the AAA ATPases with or without ligand. The distances from ADP to the His20 in the His-Ser-His motif and the Arg finger (Arg353 or Arg378) in both RUVBL1/2 complex structures bound with or without ADP have significant differences, suggesting dramatically different interactions of the binding site with ADP. Taken together, the inhibitors of six well-studied AAA ATPases and their structural information suggest further development of specific AAA ATPase inhibitors due to difference in their structures. Future chemical biology coupled with proteomic approaches could be employed to develop variant specific, complex specific, and pathway specific inhibitors or activators for AAA ATPase proteins.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.ejmech.2021.113446DOIArticle
ORCID:
AuthorORCID
Zhang, Gang0000-0003-0774-5710
Cheng, Kai-Wen0000-0001-9888-9773
Chou, Tsui-Fen0000-0003-2410-2186
Additional Information:© 2021 Elsevier Masson SAS. Received 6 October 2020, Revised 21 March 2021, Accepted 30 March 2021, Available online 10 April 2021. AAA ATPase related work in the Chou lab was funded in part by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, R01NS100815 and R01NS102279; National Institute of Child Health and Human Development R01 HD086596. Work on p97 in the authors’ laboratories has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024, Task Order No. 75N091019F00129. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funders:
Funding AgencyGrant Number
NIHR01NS100815
NIHR01NS102279
NIHR01 HD086596
NIH75N91019D00024
NIH75N091019F00129
National Cancer InstituteUNSPECIFIED
Subject Keywords:AAA ATPases; Small molecule inhibitors; p97; RUVBL1/2; ATAD2
DOI:10.1016/j.ejmech.2021.113446
Record Number:CaltechAUTHORS:20210413-071559531
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210413-071559531
Official Citation:Gang Zhang, Shan Li, Kai-Wen Cheng, Tsui-Fen Chou, AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors, European Journal of Medicinal Chemistry, Volume 219, 2021, 113446, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2021.113446. (https://www.sciencedirect.com/science/article/pii/S0223523421002956)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108705
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:13 Apr 2021 23:29
Last Modified:21 Apr 2021 17:46

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