Monecke, Thomas

[["dc.bibliographiccitation.artnumber","e90915"],["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.lastpage","13"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Monecke, Thomas"],["dc.contributor.author","Buschmann, Juliane"],["dc.contributor.author","Neumann, Piotr"],["dc.contributor.author","Wahle, Elmar"],["dc.contributor.author","Ficner, Ralf"],["dc.date.accessioned","2017-09-07T11:46:28Z"],["dc.date.available","2017-09-07T11:46:28Z"],["dc.date.issued","2014"],["dc.description.abstract","5'-nucleotidases catalyze the hydrolytic dephosphorylation of nucleoside monophosphates. As catabolic enzymes they contribute significantly to the regulation of cellular nucleotide levels; misregulation of nucleotide metabolism and nucleotidase deficiencies are associated with a number of diseases. The seven human 5'-nucleotidases differ with respect to substrate specificity and cellular localization. Recently, the novel cytosolic 5'-nucleotidase III-like protein, or cN-IIIB, has been characterized in human and Drosophila. cN-IIIB exhibits a strong substrate preference for the modified nucleotide 7-methylguanosine monophosphate but the structural reason for this preference was unknown. Here, we present crystal structures of cN-IIIB from Drosophila melanogaster bound to the reaction products 7-methylguanosine or cytidine. The structural data reveal that the cytosine-and 7-methylguanine moieties of the products are stacked between two aromatic residues in a coplanar but off-centered position. 7-methylguanosine is specifically bound through p-p interactions and distinguished from unmodified guanosine by additional cation-p coulomb interactions between the aromatic side chains and the positively charged 7-methylguanine. Notably, the base is further stabilized by T-shaped edge-to-face stacking of an additional tryptophan packing perpendicularly against the purine ring and forming, together with the other aromates, an aromatic slot. The structural data in combination with site-directed mutagenesis experiments reveal the molecular basis for the broad substrate specificity of cN-IIIB but also explain the substrate preference for 7-methylguanosine monophosphate. Analyzing the substrate specificities of cN-IIIB and the main pyrimidine 59-nucleotidase cN-IIIA by mutagenesis studies, we show that cN-IIIA dephosphorylates the purine m(7)GMP as well, hence redefining its substrate spectrum. Docking calculations with cN-IIIA and m(7)GMP as well as biochemical data reveal that Asn69 does not generally exclude the turnover of purine substrates thus correcting previous suggestions."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2014"],["dc.identifier.doi","10.1371/journal.pone.0090915"],["dc.identifier.gro","3142174"],["dc.identifier.isi","000332483600105"],["dc.identifier.pmid","24603684"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10016"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/5355"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: Gottingen University; DFG"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Crystal Structures of the Novel Cytosolic 5'-Nucleotidase IIIB Explain Its Preference for m7GMP"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]