University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Molecular Medicine; Schiffer Lab

Publication Date

4-28-2017

Document Type

Article

Disciplines

Biochemistry | Enzymes and Coenzymes | Molecular Biology | Structural Biology

Abstract

Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active site poised for catalysis of APOBEC3A, but pinpoints the residues that confer specificity towards CC/TC motifs. The APOBEC3A-ssDNA complex defines the 5'-3' directionality and subtle conformational changes that clench the ssDNA within the binding groove, revealing the architecture and mechanism of ssDNA recognition that is likely conserved among all polynucleotide deaminases, thereby opening the door for the design of mechanistic-based therapeutics.

Rights and Permissions

Copyright The Author(s) 2017. Citation: Nat Commun. 2017 Apr 28;8:15024. doi: 10.1038/ncomms15024. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Keywords

APOBEC3A, crystal structure, cytidine deaminase

Journal/Book/Conference Title

Nature communications

PubMed ID

28452355

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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