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Related Concept Videos

Mutations01:39

Mutations

Overview
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart, a...
Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
Pre-mRNA Processing: Modification of pre-mRNA Ends01:35

Pre-mRNA Processing: Modification of pre-mRNA Ends

In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
Once about 20-40 ribonucleotides have been joined together by RNA polymerase, a group of enzymes adds a cap to the 5' end of the growing transcript. In this process, a 5' phosphate is replaced by modified guanosine that has a methyl group attached (7-methyl guanosine). This 5' cap helps the cell...
Point and Frameshift Mutations01:30

Point and Frameshift Mutations

Point mutations are genetic alterations involving the change of a single nucleotide base pair in DNA. Depending on how the alteration affects protein synthesis, they can lead to various consequences.Point mutations fall into the following types:Silent mutations occur when a nucleotide change does not alter the amino acid sequence due to the redundancy of the genetic code. For instance, changing ACC to ACA still encodes threonine, leaving the protein function unaffected. This occurs because...

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Related Experiment Video

Updated: May 10, 2026

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins
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Neo-Cysteine Molecular Glues for Targeting Mutated SMAD4 Protein.

Pooja Kumari1, Yoon Hyeun Oum1,2, Eric J Miller1,3

  • 1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA.

Angewandte Chemie (International Ed. in English)
|January 2, 2026
PubMed
Summary

Researchers discovered a novel molecular glue that targets neo-cysteine residues to restore protein interactions disrupted by mutations. This approach offers a new strategy for precision medicine, particularly in cancer treatment.

Keywords:
Activity‐based protein profilingCovalent drugsMolecular gluesNeo‐cysteineProtein–protein interactions

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Chemical Biology

Background:

  • Neo-protein-protein interactions (neoPPIs) driven by mutations are key targets in precision medicine.
  • Small molecules can act as molecular glues to mediate neoPPIs, reprogramming cellular functions.
  • Neo-cysteine at protein-protein interaction interfaces offers unique opportunities for covalent molecular glues.

Purpose of the Study:

  • To discover novel neo-cysteine molecular glues (neoCMGs) for targeting mutation-disrupted protein-protein interactions.
  • To establish a screening approach for identifying neoCMGs using SMAD4 as a model system.

Main Methods:

  • Developed a robust protein-protein interaction (PPI) biosensor assay for high-throughput chemical screening.
  • Employed systematic chemical screening to identify potential neoCMGs.
  • Conducted biophysical and biochemical characterization of identified compounds.

Main Results:

  • Identified neoCMG101, a novel neoCMG, through unbiased chemical screening.
  • Demonstrated that neoCMG101 selectively and covalently modifies the neo-C361 residue on SMAD4.
  • Showed that neoCMG101 enhances SMAD4-R361C/SMAD3 PPI and restores SMAD-dependent transcriptional activity.

Conclusions:

  • Established the feasibility of using neo-cysteine-directed molecular glues to restore mutant PPIs.
  • Validated a generalizable strategy for identifying neoCMG hits through unbiased screening.
  • Provided a framework for targeting mutation-disrupted signaling networks in cancer and other diseases using neoCMGs.