Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets
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 co...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54409-5 |
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| author | Martin P. Schwalm Johannes Dopfer Adarsh Kumar Francesco A. Greco Nicolas Bauer Frank Löhr Jan Heering Sara Cano-Franco Severin Lechner Thomas Hanke Ivana Jaser Viktoria Morasch Christopher Lenz Daren Fearon Peter G. Marples Charles W. E. Tomlinson Lorene Brunello Krishna Saxena Nathan B. P. Adams Frank von Delft Susanne Müller Alexandra Stolz Ewgenij Proschak Bernhard Kuster Stefan Knapp Vladimir V. Rogov |
| author_facet | Martin P. Schwalm Johannes Dopfer Adarsh Kumar Francesco A. Greco Nicolas Bauer Frank Löhr Jan Heering Sara Cano-Franco Severin Lechner Thomas Hanke Ivana Jaser Viktoria Morasch Christopher Lenz Daren Fearon Peter G. Marples Charles W. E. Tomlinson Lorene Brunello Krishna Saxena Nathan B. P. Adams Frank von Delft Susanne Müller Alexandra Stolz Ewgenij Proschak Bernhard Kuster Stefan Knapp Vladimir V. Rogov |
| author_sort | Martin P. Schwalm |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0ff8e2e78f01471696adb4f0f5d9be05 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0ff8e2e78f01471696adb4f0f5d9be052024-12-01T12:35:23ZengNature PortfolioNature Communications2041-17232024-11-0115111510.1038/s41467-024-54409-5Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pocketsMartin P. Schwalm0Johannes Dopfer1Adarsh Kumar2Francesco A. Greco3Nicolas Bauer4Frank Löhr5Jan Heering6Sara Cano-Franco7Severin Lechner8Thomas Hanke9Ivana Jaser10Viktoria Morasch11Christopher Lenz12Daren Fearon13Peter G. Marples14Charles W. E. Tomlinson15Lorene Brunello16Krishna Saxena17Nathan B. P. Adams18Frank von Delft19Susanne Müller20Alexandra Stolz21Ewgenij Proschak22Bernhard Kuster23Stefan Knapp24Vladimir V. Rogov25Institute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Biophysical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7Institute of Biochemistry II (IBC2), Faculty of Medicine, Goethe UniversityChair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of MunichInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtNanoTemper Technologies GmbHInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtDiamond Light Source Ltd., Harwell Science and Innovation CampusDiamond Light Source Ltd., Harwell Science and Innovation CampusDiamond Light Source Ltd., Harwell Science and Innovation CampusInstitute of Biochemistry II (IBC2), Faculty of Medicine, Goethe UniversityInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtNanoTemper Technologies GmbHDiamond Light Source Ltd., Harwell Science and Innovation CampusInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute of Biochemistry II (IBC2), Faculty of Medicine, Goethe UniversityInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtChair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of MunichInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtInstitute for Pharmaceutical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Goethe University FrankfurtAbstract 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.https://doi.org/10.1038/s41467-024-54409-5 |
| spellingShingle | Martin P. Schwalm Johannes Dopfer Adarsh Kumar Francesco A. Greco Nicolas Bauer Frank Löhr Jan Heering Sara Cano-Franco Severin Lechner Thomas Hanke Ivana Jaser Viktoria Morasch Christopher Lenz Daren Fearon Peter G. Marples Charles W. E. Tomlinson Lorene Brunello Krishna Saxena Nathan B. P. Adams Frank von Delft Susanne Müller Alexandra Stolz Ewgenij Proschak Bernhard Kuster Stefan Knapp Vladimir V. Rogov Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets Nature Communications |
| title | Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets |
| title_full | Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets |
| title_fullStr | Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets |
| title_full_unstemmed | Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets |
| title_short | Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets |
| title_sort | critical assessment of lc3 gabarap ligands used for degrader development and ligandability of lc3 gabarap binding pockets |
| url | https://doi.org/10.1038/s41467-024-54409-5 |
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