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Related Concept Videos

The Proteasome02:18

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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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.
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Directing Proteins to the Rough Endoplasmic Reticulum01:34

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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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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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Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick.  Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Structure driven compound optimization in targeted protein degradation.

Thomas M Leissing1, Laura M Luh2, Philipp M Cromm2

  • 1Evotec SE, Essener Bogen 7, 22419 Hamburg, Germany.

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Summary
This summary is machine-generated.

Small molecule degraders offer a new way to remove disease proteins, not just inhibit them. Understanding the ternary complex structure is key to developing these powerful new drugs.

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Area of Science:

  • Medicinal Chemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Small molecule induced protein degradation is a rapidly advancing field in drug discovery.
  • This approach expands the druggable space beyond traditional target inhibition.
  • It relies on the formation of a ternary complex involving an E3 ubiquitin ligase, a small molecule degrader, and the target protein.

Purpose of the Study:

  • To review target protein degradation from a structural perspective.
  • To highlight the evolution of small molecule degraders based on structural insights.
  • To emphasize the importance of understanding the ternary complex structure for optimizing degradation.

Main Methods:

  • Structural analysis of ternary complexes.
  • Crystallography to capture transient protein-ligand interactions.
  • Review of existing literature on small molecule degraders and their structural characteristics.

Main Results:

  • The ternary complex is central to the ubiquitination and proteasomal degradation of target proteins.
  • Obtaining structural information of the ternary complex is challenging but crucial.
  • Structural insights have significantly improved the understanding and design of small molecule degraders.

Conclusions:

  • Structural understanding of the ternary complex is pivotal for advancing small molecule induced protein degradation.
  • The evolution of degraders is directly informed by structural data.
  • This approach holds significant promise for future drug discovery efforts.