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Related Concept Videos

The Proteasome01:13

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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Regulated Protein Degradation02:58

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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The Proteasome Structure01:17

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Covalently Linked Protein Regulators02:04

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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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Related Experiment Video

Updated: Aug 18, 2025

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using

Sridhar Radhakrishnan1, Oskar Hoff1, Markus K Muellner1

  • 1Celeris Therapeutics, Inc., Menlo Park, CA 94025, USA.

Molecules (Basel, Switzerland)
|December 11, 2022
PubMed
Summary
This summary is machine-generated.

Bivalent proximity-inducing compounds offer novel therapeutic strategies by hijacking E3 ligases for targeted protein degradation. This review explores current E3 ligases, their ligands, and associated challenges and opportunities in drug development.

Keywords:
E3 ligaseE3 recruiterPICPROTACproximity-inducing compoundtargeted protein degradationubiquitination

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Bivalent proximity-inducing compounds are a novel class of small molecule therapeutics.
  • Targeted protein degradation (TPD) is a promising therapeutic modality.
  • TPD utilizes E3 ligases to recruit substrate proteins for proteasomal degradation.

Purpose of the Study:

  • To provide an overview of E3 ligases employed in TPD.
  • To discuss ligands for these E3 ligases.
  • To highlight challenges and opportunities in the field of bivalent compounds for TPD.

Main Methods:

  • Literature review of current research on E3 ligases and TPD.
  • Analysis of existing ligands and their mechanisms of action.
  • Discussion of challenges and future directions in the development of bivalent compounds.

Main Results:

  • Overview of commonly used E3 ligases (e.g., VHL, Cereblon) in TPD.
  • Identification of various small molecule ligands that induce proximity between E3 ligases and target proteins.
  • Discussion of challenges such as off-target effects, pharmacokinetics, and resistance.

Conclusions:

  • Bivalent compounds represent a significant advancement in targeted protein degradation.
  • Further research is needed to overcome current challenges and fully realize the therapeutic potential of these compounds.
  • Optimizing E3 ligases, ligands, and delivery strategies is crucial for clinical success.