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PreprintCited by 3Protein Structure and DynamicsEnzyme Structure and FunctionComputational Drug Discovery Methods

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Regulatory interactions between APOBEC3B N- and C-terminal domains

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Braza, Mac Kevin E., Demir, Özlem, Ahn, Surl-Hee, Morris, Clare K., Calvó-Tusell, Carla, McGuire, Kelly L., de la Peña Avalos, Bárbara, Carpenter, Michael A., Chen, Yanjun, Casalino, Lorenzo, Aihara, Hideki, Herzik, Mark A., Harris, Reuben S., Amaro, Rommie E.·2024·Journal of Chemical Information and Modeling
DOI 10.1101/2024.12.11.628032PMC PMC12004528

Preprint — published as 10.1021/acs.jcim.4c02272 · Paper page

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Abstract

APOBEC3B (A3B) is implicated in DNA mutations that facilitate tumor evolution. Although structures of its individual N- and C-terminal domains (NTD and CTD) have been resolved through X-ray crystallography, the full-length A3B (fl-A3B) structure remains elusive, limiting understanding of its dynamics and mechanisms. In particular, the APOBEC3B C-terminal domain (A3Bctd) active site is frequently closed in models and structures. In this study, we built several new models of fl-A3B using integrative structural biology methods and selected a top model for further dynamical investigation. We compared dynamics of the truncated (A3Bctd) to the fl-A3B via conventional and Gaussian accelerated molecular dynamics (MD) simulations. Subsequently, we employed weighted ensemble methods to explore the fl-A3B active site opening mechanism, finding that interactions at the NTD-CTD interface enhance the opening frequency of the fl-A3B active site. Our findings shed light on the structural dynamics of fl-A3B, which may offer new avenues for therapeutic intervention in cancer.

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Metadata

Authors
Braza, M. K. E., Demir, Ö., Ahn, S.-H., Morris, C. K., Calvó-Tusell, C., McGuire, K. L., de la Peña Avalos, B., Carpenter, M. A., Chen, Y., Casalino, L., Aihara, H., Herzik, M. A., Harris, R. S., & Amaro, R. E.
Affiliations
  • University of California San Diego (US)
  • University of California, Davis (US)
  • Howard Hughes Medical Institute (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Minnesota (US)
Corresponding author
Amaro, Rommie E.
ORCID
Venue
Journal of Chemical Information and Modeling
Publisher
openRxiv
Published
2024-12-12
Volume
65
Issue
7
Pages
3593-3604
ISSN
1549-9596 (ISSN-L)
DOI
10.1101/2024.12.11.628032
PMC
PMC12004528
OpenAlex
W4408588993
Cited by
3
References
1
Citations by year
2026: 1 · 2025: 2
FWCI
0.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Chemical Information and Modeling (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
Funders
  • University of California, Davis
  • National Cancer Institute (T32CA009523, P01CA234228)
  • National Institute of General Medical Sciences (R35GM118047)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
APOBEC3B, C-terminal domain, N-terminal domain, full-length protein structure, integrative structural biology, protein dynamics, allosteric site, druggability, DNA mutagenesis, cancer therapy

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