Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14.
Marion SchullerKerstin RiedelIan Gibbs-SeymourKristin UthChristian SiegAndré P GehringIvan AhelFranz BracherBenedikt M KesslerJonathan M ElkinsStefan KnappPublished in: ACS chemical biology (2017)
Macrodomains are conserved protein interaction modules that can be found in all domains of life including in certain viruses. Macrodomains mediate recognition of sequence motifs harboring 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 characterization of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallization 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 localization to sites of DNA damage.
Keyphrases
- small molecule
- dna damage
- protein protein
- dna repair
- molecular dynamics
- oxidative stress
- induced apoptosis
- endothelial cells
- papillary thyroid
- sars cov
- cell cycle arrest
- squamous cell carcinoma
- amino acid
- binding protein
- induced pluripotent stem cells
- mouse model
- structural basis
- cell death
- young adults
- squamous cell
- risk assessment
- endoplasmic reticulum stress
- network analysis