4R5W

Human artd1 (parp1) - catalytic domain in complex with inhibitor xav939

Summary for 4R5W

• Entry DOI: 10.2210/pdb4r5w/pdb
• Related: 4R6E 4UND 4UXB
• Descriptor: Poly [ADP-ribose] polymerase 1, SULFATE ION, 2-[4-(trifluoromethyl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, ... (4 entities in total)
• Functional Keywords: adp-ribosylation, dna repair, adp-ribosyl transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P09874
• Total number of polymer chains: 2
• Total formula weight: 81696.96

Authors

Karlberg, T.,Thorsell, A.G.,Schuler, H. (deposition date: 2014-08-22, release date: 2015-09-02, Last modification date: 2023-09-20)

Primary citation

Thorsell, A.G.,Ekblad, T.,Karlberg, T.,Low, M.,Pinto, A.F.,Tresaugues, L.,Moche, M.,Cohen, M.S.,Schuler, H.
Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
J.Med.Chem., 60:1262-1271, 2017

PubMed Abstract: Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

PubMed: 28001384
DOI: 10.1021/acs.jmedchem.6b00990

Experimental method

X-RAY DIFFRACTION (2.84 Å)