Crystal structure of a covalently linked Aurora-A-MYCN complex
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Updated: Aug 15, 2025
Analyzing Protein Architectures and Protein-Ligand Complexes by Integrative Structural Mass Spectrometry
Published on: October 15, 2018
Mathias Diebold1, Lars Schönemann2, Martin Eilers3
1Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Abstract:
Formation of the Aurora-A-MYCN complex increases levels of the oncogenic transcription factor MYCN in neuroblastoma cells by abrogating its degradation through the ubiquitin proteasome system. While some small-molecule inhibitors of Aurora-A were shown to destabilize MYCN, clinical trials have not been satisfactory to date. MYCN itself is considered to be `undruggable' due to its large intrinsically disordered regions. Targeting the Aurora-A-MYCN complex rather than Aurora-A or MYCN alone will open new possibilities for drug development and screening campaigns. To overcome the challenges that a ternary system composed of Aurora-A, MYCN and a small molecule entails, a covalently cross-linked construct of the Aurora-A-MYCN complex was designed, expressed and characterized, thus enabling screening and design campaigns to identify selective binders.
Insights
Researchers created a stable Aurora-A-MYCN complex to develop new drugs for neuroblastoma. This approach targets the complex to overcome challenges in inhibiting the oncogenic MYCN protein.
Area of Science:
- Molecular biology
- Oncology
- Drug discovery
Background:
- The Aurora-A-MYCN complex elevates MYCN levels in neuroblastoma by blocking its degradation.
- Current Aurora-A inhibitors have shown limited success in clinical trials.
- MYCN is considered 'undruggable' due to its disordered structure.
Purpose of the Study:
- To develop novel therapeutic strategies for neuroblastoma by targeting the Aurora-A-MYCN complex.
- To create a stable, cross-linked Aurora-A-MYCN complex for drug screening.
- To enable the identification of selective binders for the Aurora-A-MYCN complex.
Main Methods:
- Design and construction of a covalently cross-linked Aurora-A-MYCN complex.
- Expression and characterization of the cross-linked complex.
- Establishment of a platform for drug screening and design campaigns.
Main Results:
- A stable, covalently cross-linked Aurora-A-MYCN complex was successfully generated.
- The characterized complex serves as a tool for identifying novel therapeutic agents.
- This approach facilitates screening for selective binders against the complex.
Conclusions:
- Targeting the Aurora-A-MYCN complex offers a promising new avenue for neuroblastoma drug development.
- The cross-linked complex overcomes challenges associated with targeting intrinsically disordered proteins.
- This strategy opens possibilities for new drug screening and design campaigns.
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