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Updated: Jan 13, 2026
Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
Published on: April 27, 2017
Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1
Alessia Vincenza Florio1, Corinne Buré2, Sébastien Fribourg3
1INSERM U1212, CNRS UMR5320, Université de Bordeaux, 2 Rue Hoffmann Martinot, 33000 Bordeaux, France; Department of Biological, Chemical and Pharmaceutical Sciences and Technology, University of Palermo, Via Archirafi 28, Palermo, Italy.
Abstract:
Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.
Insights
Researchers detailed how a small molecule, (R)-SKBG-1, specifically targets the NONO protein, an RNA-binding protein implicated in cancer. This structural and binding analysis provides a foundation for developing new cancer drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- RNA-binding proteins (RBPs) play crucial roles in cellular functions and are linked to genetic diseases.
- NONO, an RBP involved in mRNA splicing, DNA repair, and organelle stability, is a target for cancer drug development.
- Small-molecule inhibitors targeting NONO have been identified.
Purpose of the Study:
- To elucidate the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1.
- To determine the specific binding interaction between (R)-SKBG-1 and NONO.
- To investigate the enantiomer selectivity of this interaction.
Main Methods:
- Mass spectrometry measurements to analyze binding.
- Crystal structure determination of the (R)-SKBG-1-NONO homodimer complex.
- Analysis of conformational changes upon binding.
Main Results:
- The study determined the crystal structure of the NONO homodimer bound to (R)-SKBG-1.
- Specific binding of (R)-SKBG-1 to NONO was confirmed.
- Conformational plasticity of (R)-SKBG-1 upon covalent binding to NONO was revealed.
Conclusions:
- The findings provide a detailed molecular understanding of (R)-SKBG-1 interaction with NONO.
- This structural insight offers an experimental rationale for designing and optimizing NONO-targeting ligands.
- The results support the potential development of (R)-SKBG-1 or its derivatives as anti-cancer therapeutics.
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