Schwalm, Martin P, Dopfer, Johannes, Kumar, Adarsh et al. (23 more authors) (2024) Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets. Nature Communications. 10204. ISSN 2041-1723
Abstract
Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024. The Author(s). |
Keywords: | Microtubule-Associated Proteins/metabolism,Ligands,Humans,Apoptosis Regulatory Proteins/metabolism,Binding Sites,Molecular Docking Simulation,Adaptor Proteins, Signal Transducing/metabolism,Autophagosomes/metabolism,Protein Binding,Autophagy,Crystallography, X-Ray |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 28 Nov 2024 11:30 |
Last Modified: | 02 Dec 2024 01:18 |
Published Version: | https://doi.org/10.1038/s41467-024-54409-5 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-024-54409-5 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:220216 |
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Filename: s41467-024-54409-5.pdf
Description: Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets.
Licence: CC-BY 2.5