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Regulatory interactions between APOBEC3B N- and C-terminal domains.
Mac Kevin E Braza1, Özlem Demir1, Surl-Hee Ahn2
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA.
Biorxiv : the Preprint Server for Biology
|December 23, 2024
Summary
The full-length APOBEC3B (A3B) protein's active site opens more frequently due to interactions between its domains. This structural insight into A3B dynamics may reveal new cancer therapy targets.
Area of Science:
- Structural Biology
- Molecular Dynamics
- Cancer Research
Background:
- APOBEC3B (A3B) DNA deaminase is crucial in tumor evolution via DNA mutations.
- Previous studies resolved individual N- and C-terminal domains (NTD/CTD) of A3B but not the full-length (fl-A3B).
- The A3B C-terminal domain (A3Bctd) active site is often observed in a closed conformation, hindering mechanistic understanding.
Purpose of the Study:
- To elucidate the structural dynamics of full-length APOBEC3B (fl-A3B).
- To investigate the active site opening mechanism of fl-A3B and compare it to the truncated A3Bctd.
- To identify how domain interactions influence A3B's conformational flexibility.
Main Methods:
- Integrative structural biology for fl-A3B model building.
- Conventional and Gaussian accelerated molecular dynamics (MD) simulations.
- Weighted ensemble methods to explore active site dynamics.
Main Results:
- Developed and refined models of fl-A3B.
- Compared dynamics between fl-A3B and A3Bctd.
- Identified that NTD-CTD interface interactions increase the frequency of fl-A3B active site opening.
Conclusions:
- The structural dynamics of fl-A3B are influenced by inter-domain interactions.
- The enhanced active site opening in fl-A3B provides new insights into A3B mechanisms.
- Findings may inform the development of novel therapeutic strategies targeting A3B in cancer.
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