UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences; Schiffer Lab
Publication Date
2018-11-20
Document Type
Article Postprint
Disciplines
Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology
Abstract
APOBEC3s proteins (A3s), a family of human cytidine deaminases, protect the host from endogenous retro-elements and exogenous viral infections by introducing hypermutations. However, overexpressed A3s can modify genomic DNA to promote tumorigenesis, especially A3B. Despite overall similarity, A3 proteins have distinct deamination activity. Recently determined A3 structures have revealed the molecular determinants of nucleotide specificity and DNA binding. However, for A3B, the structural basis for regulation of deamination activity and the role of active site loops in coordinating DNA had remained unknown. Using advanced molecular modeling followed by experimental mutational analysis and dynamics simulations, we investigated molecular mechanism of DNA binding by A3B-CTD. We modeled fully native A3B-DNA structure, identified Arg211 in loop 1 as the gatekeeper coordinating DNA and critical residues for nucleotide specificity. We also identified a unique auto-inhibited conformation in A3B-CTD that restricts access and binding of DNA to the active site. Our results reveal the structural basis for DNA binding and relatively lower catalytic activity of A3B and provide opportunities for rational design of specific inhibitors to benefit cancer therapeutics.
Keywords
APOBEC3, structural analysis and modeling, DNA binding, molecular dynamics simulations
Rights and Permissions
This document is the Accepted Manuscript version of a Published Work that appeared in final form in J Chem Theory Comput., copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jctc.8b00545. Accepted manuscript posted after 12 months as allowed by publisher's Journal Publishing Agreement User’s Guide at https://pubs.acs.org/userimages/ContentEditor/1285231362937/jpa_user_guide.pdf.
DOI of Published Version
10.1021/acs.jctc.8b00545
Source
J Chem Theory Comput. 2018 Nov 20. doi: 10.1021/acs.jctc.8b00545. [Epub ahead of print] Link to article on publisher's site
Journal/Book/Conference Title
Journal of chemical theory and computation
Related Resources
PubMed ID
30457868
Repository Citation
Hou, Shurong; Silvas, Tania V.; Leidner, Florian; Nalivaika, Ellen A.; Matsuo, Hiroshi; Yilmaz, Nese Kurt; and Schiffer, Celia A., "Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B" (2018). Schiffer Lab Publications. 30.
https://escholarship.umassmed.edu/schiffer/30
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Cancer Biology Commons, Enzymes and Coenzymes Commons, Medicinal Chemistry and Pharmaceutics Commons, Medicinal-Pharmaceutical Chemistry Commons, Molecular Biology Commons, Structural Biology Commons