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ADP-ribose can be conjugated to proteins singly as\u00a0a monomer or in polymeric chains as poly(ADP-ribose). While ADP-ribosylation can be reversed by ADP-ribosylhydrolases, this protein modification can also be processed to phosphoribosylation by enzymes possessing phosphodiesterase activity, such as snake venom phosphodiesterase, mammalian ectonucleotide pyrophosphatase\/phosphodiesterase 1, <jats:italic>Escherichia coli<\/jats:italic> RppH, <jats:italic>Legionella pneumophila<\/jats:italic> Sde and <jats:italic>Homo sapiens<\/jats:italic> NudT16 (<jats:italic>Hs<\/jats:italic>NudT16). Our studies here sought to utilize X-ray crystallographic structures of <jats:italic>Hs<\/jats:italic>NudT16 in complex with monomeric and dimeric ADP-ribose in identifying the active site for binding and processing free and protein-conjugated ADP-ribose into phosphoribose forms. These structural data guide rational design of mutants that widen the active site to better accommodate protein-conjugated ADP-ribose. We identified that several <jats:italic>Hs<\/jats:italic>NudT16 mutants (\u039417, F36A, and F61S) have reduced activity for free ADP-ribose, similar processing ability against protein-conjugated mono(ADP-ribose), but improved catalytic efficiency for protein-conjugated poly(ADP-ribose). These <jats:italic>Hs<\/jats:italic>NudT16 variants may, therefore, provide a novel tool to investigate different forms of ADP-ribose.<\/jats:p>","DOI":"10.1038\/s41598-019-39491-w","type":"journal-article","created":{"date-parts":[[2019,4,11]],"date-time":"2019-04-11T10:15:44Z","timestamp":1554977744000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Structural analyses of NudT16\u2013ADP-ribose complexes direct rational design of mutants with improved processing of poly(ADP-ribosyl)ated proteins"],"prefix":"10.1038","volume":"9","author":[{"given":"Puchong","family":"Thirawatananond","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-889X","authenticated-orcid":false,"given":"Robert Lyle","family":"McPherson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmine","family":"Malhi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-0303","authenticated-orcid":false,"given":"Sara","family":"Nathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Lambrecht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1683-9196","authenticated-orcid":false,"given":"Matthew","family":"Brichacek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul J.","family":"Hergenrother","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5569-4036","authenticated-orcid":false,"given":"Anthony K. 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