The human family of Diphtheria toxin related ADP-ribosyltransferases (ARTDs) catalyze the transfer of ADP-ribose units onto their substrate proteins. These transferases fall into two major subfamilies; mARTs mono-ADP-ribosylate their targets, whereas PARPs transfer units onto growing chains of ADP-ribose on their tagets. While mART activity is largely enigmatic, PARP activity has a documented role in chromatin remodeling and DNA repair; both subfamilies are implicated in epigenetic signaling events. Our main focus is to study the role of ADP-ribosylation, a common post-translational modification observed on histones and other nuclear proteins, and we work mainly, but not exclusively, on ADP-ribose transferases of the PARP class.

The multidisciplinary project adopts a protein family wide approachs and  is based upon previous work within the Structural Genomics Consortium (SGC). The project is a collaboration with the labs of Prof. Mikael Elofsson and Dr. Anna Linusson at Umeå University and affiliated to the SGC chemical probes for epigenetics project.

Funding: The Swedish Foundation for Strategic Research

Family wide chemical profiling of PARP inhibitors. Principal component analysis of the complete screening data set showing the activity space of PARP inhibitors according to the first and second components. Positive values of component F1 indicate stabilization of PARP1-4, and positive values of component F2 indicate stabilization of TNKS1-2. Green indicates the PARP1-4 selective, yellow the unselective and red the tankyrase-selective primary hit compounds.
Published in Wahlberg et al. Nature Biotechnology, 2012
Press release (in swedish)

TNKS2 in complex with the potent inhibitor XAV939, PARP2 (in blue) superimposed onto the occupied ligand binding pocket, illustrating the positioning of α-helix-5 of the regulatory domain near the NAD+ cleft opening, and conserved side chains in the nicotinamide binding crevice. Published in Karlberg et al 2010. PMID: 20565110

Wahlberg E*, Karlberg T*, Kouznetsova E*, Markova N, Macchiarulo A, Thorsell AG, Pol E, Frostell Å, Ekblad T, Öncü D, Kull B, Robertson GM, Pellicciari R, Schüler H, Weigelt J. Family wide chemical profiling and structural analysis of PARP and Tankyrase inhibitors. Nature Biotechnology 2012. PMID: 22343925

Karlberg T, Markova N, Johansson I, Hammarström M, Schütz P, Weigelt J, Schüler H. Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor. Journal of Medicinal Chemistry 2010. PMID: 20565110

Hottiger MO, Hassa PO, Lüscher B, Schüler H, Koch-Nolte F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends in Biochemical Sciences 2010. PMID: 20106667

Karlberg T, Hammarström M, Schütz P, Svensson L, Schüler H. Crystal structure of the catalytic domain of human PARP2 in complex with PARP inhibitor ABT-888. Biochemistry 2010. PMID: 20092359

Loseva O, Jemth AS, Bryant HE, Schüler H, Lehtiö L, Karlberg T, Helleday T. Poly(ADP-ribose) polymerase-3 (PARP-3) is a mono-ADP ribosylase that activates PARP-1 in absence of DNA. Journal of Biological Chemistry 2010. PMID: 20064938

Lehtiö L, Jemth AS, Collins R, Loseva O, Johansson A, Markova N, Hammarström M, Flores A, Holmberg-Schiavone L, Weigelt J, Helleday T, Schüler H, Karlberg T. Structural basis for inhibitor specificity in human poly(ADP-ribose) polymerase-3. Journal of Medicinal Chemistry 2009. PMID: 19354255

Lehtiö L, Collins R, van den Berg S, Johansson A, Dahlgren L-G, Hammarström M, Helleday T, Holmberg-Schiavone L, Karlberg T and Weigelt J. Zinc binding catalytic domain of human tankyrase 1. Journal of Molecular Biology 2008. PMID: 18436240

Structures

We have solved crystal structures of catalytic domains and macro domains of human PARP family members, several of them in complex with inhibitors in the active sites. Click for structures.