UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences; Schiffer Lab

Publication Date


Document Type

Article Postprint


Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology


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.


APOBEC3, structural analysis and modeling, DNA binding, molecular dynamics simulations

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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 Accepted manuscript posted after 12 months as allowed by publisher's Journal Publishing Agreement User’s Guide at

DOI of Published Version



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

Link to Article in PubMed

PubMed ID