Application of AlphaFold models in evaluating ligandable cysteines across E3 ligases.
Proteins
; 92(7): 819-829, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38337153
ABSTRACT
Proteolysis Targeting Chimeras (PROTACs) are an emerging therapeutic modality and chemical biology tools for Targeted Protein Degradation (TPD). PROTACs contain a ligand targeting the protein of interest, a ligand recruiting an E3 ligase and a linker connecting these two ligands. There are over 600 E3 ligases known so far, but only a handful have been exploited for TPD applications. A key reason for this is the scarcity of ligands binding various E3 ligases and the paucity of structural data available, which complicates ligand design across the family. In this study, we aim to progress PROTAC discovery by proposing a shortlist of E3 ligases that can be prioritized for covalent targeting by performing systematic structural ligandability analysis on a chemoproteomic dataset of potentially reactive cysteines across hundreds of E3 ligases. One of the goals of this study is to apply AlphaFold (AF) models for ligandability evaluations, as for a vast majority of these ligases an experimental structure is not available in the protein data bank (PDB). Using a combination of pocket features, AF model quality and additional aspects, we propose a shortlist of E3 ligases and corresponding cysteines that can be prioritized to potentially discover covalent ligands and expand the PROTAC toolbox.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Unión Proteica
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Cisteína
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Ubiquitina-Proteína Ligasas
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Proteolisis
Límite:
Humans
Idioma:
En
Revista:
Proteins
Asunto de la revista:
BIOQUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Bélgica