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Discovery of a selective allosteric inhibitor targeting macrodomain 2 of poly-adenosine-diphosphate-ribose polymerases 14

DOI: 10.1021/acschembio.7b00445 DOI Help

Authors: Marion Schuller (Structural Genomic Consortium, University of Oxford; Target Discovery Institute (TDI)) , Kerstin Riedel (University of Munich) , Ian Gibbs-Seymour (University of Oxford) , Kristin Uth (Structural Genomic Consortium, University of Oxford) , Christian Sieg (Structural Genomic Consortium, University of Oxford) , André P Gehring (University of Munich) , Ivan Ahel (University of Oxford) , Franz Bracher (University of Munich) , Benedikt M. Kessler (Target Discovery Institute (TDI), University of Oxford) , Jonathan M. Elkins (Structural Genomic Consortium, University of Oxford) , Stefan Knapp (Structural Genomic Consortium, University of Oxford; Goethe University; German Cancer Network (DKTK))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: October 2017

Abstract: Macrodomains are conserved protein interaction modules that can be found in all domains of life as well as in certain viruses. Macrodomains mediate recognition of sequence motifs harbouring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterisation of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallisation of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prevents its localisation to sites of DNA damage.

Journal Keywords: small molecule inhibitor; macrodomain; ADP-ribosylation; PARP14; DNA damage; allosteric inhibition

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography

Added On: 16/10/2017 11:48

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)