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Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	Engineering Af1521 improves ADP-ribose binding and identification of ADP-ribosylated proteins Kathrin Nowak , Florian Rosenthal , Tobias Karlberg , Mareike Bütepage , Ann-Gerd Thorsell , Birgit Dreier , Jonas Grossmann , Jens Sobek , Ralph Imhof , Bernhard Lüscher , Herwig Schüler , Andreas Plückthun , Deena M. Leslie Pedrioli , Michael O. Hottiger Nature Communications 11 DOI: 10.1038/s41467-020-18981-w Diamond Proposal Number(s): [15806] Open Access Show Abstract ▼ Abstract: Protein ADP-ribosylation is a reversible post-translational modification that regulates important cellular functions. The identification of modified proteins has proven challenging and has mainly been achieved via enrichment methodologies. Random mutagenesis was used here to develop an engineered Af1521 ADP-ribose binding macro domain protein with 1000-fold increased affinity towards ADP-ribose. The crystal structure reveals that two point mutations K35E and Y145R form a salt bridge within the ADP-ribose binding domain. This forces the proximal ribose to rotate within the binding pocket and, as a consequence, improves engineered Af1521 ADPr-binding affinity. Its use in our proteomic ADP-ribosylome workflow increases the ADP-ribosylated protein identification rates and yields greater ADP-ribosylome coverage. Furthermore, generation of an engineered Af1521 Fc fusion protein confirms the improved detection of cellular ADP-ribosylation by immunoblot and immunofluorescence. Thus, this engineered isoform of Af1521 can also serve as a valuable tool for the analysis of cellular ADP-ribosylation under in vivo conditions.	Dec 2020
I04-Macromolecular Crystallography	A PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3 Anders E. G. Lindgren , Tobias Karlberg , Ann-Gerd Thorsell , Mareike Hesse , Sara Spjut , Torun Ekblad , C. David Andersson , Ana Filipa Pinto , Johan Weigelt , Michael O. Hottiger , Anna Linusson , Mikael Elofsson , Herwig Schüler Acs Chemical Biology 8 (8) DOI: 10.1021/cb4002014 PMID: 23742272 Diamond Proposal Number(s): [6603] Show Abstract ▼ Abstract: Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.	Jun 2013

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