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dc.contributor.authorHou, Shurong
dc.contributor.authorSilvas, Tania V.
dc.contributor.authorLeidner, Florian
dc.contributor.authorNalivaika, Ellen A.
dc.contributor.authorMatsuo, Hiroshi
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorSchiffer, Celia A.
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:23:06Z
dc.date.available2022-08-23T17:23:06Z
dc.date.issued2018-11-20
dc.date.submitted2018-11-26
dc.identifier.citation<p>J Chem Theory Comput. 2018 Nov 20. doi: 10.1021/acs.jctc.8b00545. [Epub ahead of print] <a href="https://doi.org/10.1021/acs.jctc.8b00545">Link to article on publisher's site</a></p>
dc.identifier.issn1549-9618 (Linking)
dc.identifier.doi10.1021/acs.jctc.8b00545
dc.identifier.pmid30457868
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48885
dc.description.abstractAPOBEC3s 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30457868&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsThis 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.
dc.subjectAPOBEC3
dc.subjectstructural analysis and modeling
dc.subjectDNA binding
dc.subjectmolecular dynamics simulations
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectCancer Biology
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.titleStructural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B
dc.typeAccepted Manuscript
dc.source.journaltitleJournal of chemical theory and computation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1029&amp;context=schiffer&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/schiffer/30
dc.legacy.embargo2019-11-20T00:00:00-08:00
dc.identifier.contextkey13368307
refterms.dateFOA2022-08-23T17:23:06Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathschiffer/30
dc.contributor.departmentSchiffer Lab
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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