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. 2023 Mar 30;22:62. doi: 10.1186/s12943-022-01707-5

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — PROTACs induce catalytic proteasomal degradation of their targets. PROTACs are heterobifunctional compounds comprised of a ligand for a target protein and a ligand for an E3 ligase joined by a linker. Simultaneous binding of a target protein and an E3 ligase promotes the formation of ternary complexes: Target-PROTAC-E3 Ligase. E3 ligases serve as adaptor proteins for E2 ligases by conferring selective target recruitment. E2 ligases receive activated ubiquitin tags from E1 ligase and conjugate ubiquitin to surface lysine residues of the target protein. Ubiquitin tags may also be ligated to pre-existing ubiquitin tags to form polyubiquitin chains. Ternary complexes may dissociate after target ubiquitylation to enable iterative target degradation by a single PROTAC molecule. Polyubiquitylated targets are recognized by the 26S proteosome where they are degraded. Image created in Biorender and Chemdraw